Anti-ischemic 2,4-diaminoquinazolines

ABSTRACT

The invention is directed to certain 2,4-diaminoquinazoline compounds, their pharmaceutically acceptable salts, the pharmaceutical compositions comprising those compounds and their therapeutic methods of use. The compounds possess anti-ischemic activity.

This is the national phase of PCT/JP92/01258, filed Sep. 30, 1991 and published as WO93/07214 Apr. 15, 1993.

FIELD OF THE INVENTION

The present invention relates to a nitrogeous heterocyclic compound having an excellent activity as a drug.

BACKGROUND OF THE INVENTION AND PRIOR ART

Angina pectoris which is one of ischemic heart diseases has been known as a disease which often attacks the aged. Although nitric and nitrous acid compounds, calcium antagonists and β-blocker have been used as therapeutic agents therefor, the effect of such a therapeutic agent is far insufficient to treat angina pectoris or to prevent the evolution thereof into myocardial infarction. Recently, the age of a patient with angina pectoris has lowered and the symptom thereof has become complicated owing to change in the style of living, stress increased by the complication of society and so forth, so that a new type of more excellent drug has been desired eagerly.

It is believed that cyclic GMP (hereinafter abbreviated to "cGMP") which is one of cyclic nucleotides and is known as an intracellular second messenger participates in the action of the nitric and nitrous acid compounds among the above drugs which are now used. The relaxing effect of cGMP on the smooth muscle of vessel and bronchus is well known. Although the mechanism of action of these drugs are not always apparent, it is generally presumed that the activity of this cGMP results from the acceleration of the synthesis of cGMP which is caused by the activation of guanylate cyclase. However, the above-mentioned drugs exhibit a low bioavailability and a relatively short time of action. Further, it is reported that the drug resistance is induced, which is a problem in a clinical field.

Under these circumstances, the present inventors have started studies to develop a new type of more excellent drug.

That is, the present inventors have paid their attention to cGMP phosphodiesterase (hereinafter abbreviated to "cGMP-PDE")-inhibiting activity and have made extensive studies on compounds having such an activity for many years. As a result of the studies, they have found that a nitrogenous heterocyclic compound which will be described below has such an activity to be efficacious for various ischemic heart diseases and have accomplished the present invention.

Although quinazoline derivatives useful as drugs are included in, e.g., Publication of International Patent Application by Japanese No. 502462/1990, they are different from the compounds of the present invention in respect of both structure and activity.

DISCLOSURE OF THE INVENTION

The present invention provides a nitrogenous heterocyclic compound represented by the following general formula (1) or a pharmacologically acceptable salt thereof: ##STR1## [in formula (1), ring A represents a benzene ring, a pyridine ring or a cyclohexane ring; ring B represents a pyridine ring, a pyrimidine ring or an imidazole ring.

Provided that the ring A and the ring B are combined sharing two atoms and the atoms shared may be either a carbon atom or a nitrogen atom.

In the case where the ring A is a pyridine ring and that except the case where the ring B shares the nitrogen atom of this pyridine ring to combine therewith, the ring A is represented by ##STR2##

R¹, R², R³ and R⁴, each of which may be the same or different from one another, represent each a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a halogen atom, a cycloalkyl group which may be substituted, a lower alkoxy group, a hydroxyalkyl group, a nitro group, a cyano group, an acylamino group, a carboxyl group which may be protected, a group represented by the formula ##STR3## (wherein R⁷ represents a lower alkyl group, and n represents 0 or an integer of 1 to 2), or a group represented by the formula ##STR4## (wherein R⁴⁵ and R⁴⁶, each of which may be the same or different from each other, represent each a hydrogen atom or a lower alkyl group; or R⁴⁵ and R⁴⁶ can form a ring which may contain another nitrogen atom or oxygen atom together with the nitrogen atom to which they are bonded with the proviso that this ring may be substituted); or, two of R¹, R², R³ and R⁴ may together form methylenedioxy, ethylenedioxy or a phenyl ring.

R⁵ represents a hydrogen atom, a halogen atom, a hydroxyl group, a hydrazino group, a lower alkyl group, a cycloalkyl group which may be substituted, a lower alkoxy group, a lower alkenyl group, a carboxyalkyl group which may be protected, a carboxyalkenyl group which may be protected, a hydroxyalkyl group, a carboxyl group which may be protected, a group represented by the formula ##STR5## (wherein R⁸ represents a lower alkyl group, and m represents 0 or an integer of 1 to 2), a group represented by the formula --O--R⁹ (wherein R⁹ represents a hydroxyalkyl group which may be protected, a carboxyalkyl group which may be protected or a benzyl group which may be substituted), a group represented by the formula ##STR6## (wherein R²³ represents a hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxyalkyl group or a hydroxyalkyloxy group), a heteroaryl group which may be substituted, a 1,3-benzdioxolyl group which may be substituted, a 1,4-benzdioxyl group which may be substituted, a 1,3-benzdioxolylalkyl group which may be substituted, a 1,4-benzdioxylalkyl group which may be substituted, a group represented by the formula --C(R²⁴)═X [wherein X represents an oxygen atom, a sulfur atom or a group represented by the formula ═N--R¹⁰ (wherein R¹⁰ represents a hydroxyl group, a cyano group or a carboxyalkyloxy group which may be protected); and R²⁴ represents a hydrogen atom or a lower alkyl group], or a group represented by the formula --NR¹¹ R¹² (wherein R¹¹ and R¹², each of which may be the same or different from each other, represent each a hydrogen atom, a lower alkyl group, a hydroxyalkyl group, an aminoalkyl group, a carboxyalkyl group which may be protected, an alkylcarbamoyl group, a carboxyalkylcarbamoyl group which may be protected, a heteroarylalkyl group which may be substituted, a 1,3-benzoxolylalkyl group or a 1,4-benzdioxylalkyl group; or, further, R¹¹ and R¹² can form a ring which may contain another nitrogen atom or oxygen atom together with a nitrogen atom to which they are bonded with the proviso that this ring may be substituted).

R⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a lower alkyl group, a lower alkoxy group, a lower alkenyl group, a 1,3-benzdioxolylalkyloxy group, a 1,4-benzdioxylalkyloxy group, a phenylalkyloxy group which may be substituted, a group represented by the formula ##STR7## (wherein R¹³ and R¹⁴, each of which may be the same or different from each other, represent each a hydrogen atom, a lower alkyl group or a lower alkoxy group; or, further, R¹³ and R¹⁴ may together form methylenedioxy or ethylenedioxy), a group represented by the formula ##STR8## a group represented by the formula ##STR9## a group represented by the formula ##STR10## a group represented by the formula ##STR11## (in these formulas, R¹⁵ and R¹⁶, each of which may be the same or different from each other, represent each a hydrogen atom, a lower alkyl group or a lower alkoxy group; or, further, R¹⁵ and R¹⁶ may together form methylenedioxy or ethylenedioxy), a piperidne-4-spiro-2'-dioxan-1-yl group, a group represented by the formula ##STR12## (wherein R⁴⁸ and R⁴⁹, each of which may be the same or different From each other, represent each a hydrogen atom, a lower alkyl group or a lower alkoxy group; or, further, R⁴⁸ and R⁴⁹ may together form methylenedioxy or ethylenedioxy; and Z represents a sulfur atom or an oxygen atom), a group represented by the formula ##STR13## (wherein R⁵⁰ represents a hydroxyl group, a halogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl group which may be protected, a cyano group, a hydroxyalkyl group or a carboxyalkyl group), a group represented by the formula ##STR14## [wherein R¹⁷ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkoxyalkyl group, a carboxyalkyl group which may be protected or a hydroxyalkyl group; Y represents a group represented by the formula --(CH₂)_(q) -- (wherein q is 0 or an integer of 1 to 8), or a group represented by the formula ##STR15## further, in the group represented by the formula --(CH₂)_(q) --, when q is an integer of 1 to 8, each carbon atom may have 1 to 2 substituent(s); and R¹⁸ represents a hydrogen atom, a hydroxyl group, a carboxyl group which may be protected, a cyano group, an acyl group, a heteroaryl group which may be substituted or a cycloalkyl group which may be substituted], or a group represented by the formula ##STR16## (wherein R¹⁹ represents a hydrogen atom, a lower alkyl group, a lower alkoxyalkyl group, an acyl group, a carboxyalkyl group which may be protected or a hydroxyalkyl group; R²⁰, R²¹ and R²², each of which may be the same or different from one another, represent each a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a lower alkyl group, a lower alkoxy group, a lower alkoxyalkyl group, a lower alkenyl group, an acyl group, an acylamino group, an alkylsulfonylamino group, a hydroxyiminoalkyl group, an alkyloxycarbonylamino group, an alkyloxycarbonyloxy group or a heteroaryl group which may be substituted; or, further, two of R²⁰, R²¹ and R²² may together form a saturated or unsaturated ring which may contain a nitrogen atom, a sulfur atom or an oxygen atom; and r represents 0 or an integer of 1 to 8)].

The quinazoline derivative represented by the following formula (I) or the pharmacologically acceptable salt thereof can be cited as one of the preferred embodiments of the nitrogenous heterocyclic compound represented by the formula (1) described above or the pharmacologically acceptable salt thereof: ##STR17## [in formula (I), R¹, R², R³ and R⁴, each of which may be the same or different from one another, represent each a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyalkyl group, a cyano group, an acylamino group, a carboxyl group which may be protected or a group represented by the formula ##STR18## (wherein R⁷ represents a lower alkyl group; and n represents 0 or an integer of 1 to 2), or two of R¹, R², R³ and R⁴ may together form methylenedioxy, ethylenedioxy or a phenyl ring.

R⁵ represents a hydrogen atom, a halogen atom, a hydroxyl group, a hydrazino group, a lower alkyl group, a lower alkoxy group, a lower alkenyl group, a carboxyalkyl group which may be protected, a carboxyalkenyl group which may be protected, a hydroxyalkyl group, a carboxyl group which may be protected, a group represented by the formula ##STR19## (wherein R⁸ represents a lower alkyl group, and m represents 0 or an integer of 1 to 2), a group represented by the formula --O--R⁹ (wherein R⁹ represents a hydroxyalkyl group which may be protected, a carboxyalkyl group which may be protected or a benzyl group), a group represented by the formula ##STR20## (wherein R²³ represents a hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxyalkyl group or a hydroxyalkyloxy group), a heteroaryl group which may be substituted, a 1,3-benzdioxolyl group which may be substituted, a 1,4-benzdioxyl group which may be substituted, a 1,3-benzdioxolylalkyl group which may be substituted, a 1,4-benzdioxylalkyl group which may be substituted, a group represented by the formula --C(R²⁴)═X [wherein X represents an oxygen atom or a group represented by the formula ═N--R¹⁰ (wherein R¹⁰ represents a hydroxyl group or a carboxyalkyloxy group which may be protected); and R²⁴ represents a hydrogen atom or a lower alkyl group], or a group represented by the formula --NR¹¹ R¹² (wherein R¹¹ and R¹², each of which may be the same or different from each other, represent each a hydrogen atom, a lower alkyl group, a hydroxyalkyl group, an aminoalkyl group, a carboxyalkyl group which may be protected, an alkylcarbamoyl group, a 1,3-benzoxolylalkyl group or a 1,4-benzdioxylalkyl group; or, further, R¹¹ and R¹² can form a ring which may contain another nitrogen atom or oxygen atom together with a nitrogen atom to which they are bonded with the proviso that this ring may be substituted).

R⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a lower alkyl group, a lower alkoxy group, a 1,3-benzdioxolylalkyloxy group, a 1,4-benzdioxylalkyloxy group, a phenylalkyloxy group which may be substituted, a group represented by the formula ##STR21## (wherein R¹³ and R¹⁴ each of which may be the same or different from each other, represent each a hydrogen atom, a lower alkyl group or a lower alkoxy group; or, further, R¹³ and R¹⁴ may together form methylenedioxy or ethylenedioxy), a group represented by the formula ##STR22## a group represented by the formula ##STR23## a group represented by the formula ##STR24## a group represented by the formula ##STR25## (in these formulas, R¹⁵ and R¹⁶ represent each a hydrogen atom, a lower alkyl group or a lower alkoxy group; or, further, R¹⁵ and R¹⁶ may together form methylenedioxy or ethylenedioxy), a piperidne-4-spiro-2'-dioxan-1-yl group or a group represented by the formula ##STR26## [wherein R¹⁷ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkoxyalkyl group, a carboxyalkyl group which may be protected or a hydroxyalkyl group; Y represents a group represented by the formula --(CH₂)_(q) -- (wherein q is 0 or an integer of 1 to 8), or a group represented by the formula ##STR27## further, in the group represented by the formula --(CH₂)_(q) --, when q is an integer of 1 to 8, each carbon atom may have 1 to 2 substituent(s); and R¹⁸ represents a hydrogen atom, a hydroxyl group, a carboxyl group which may be protected, a cyano group, an acyl group, a heteroaryl group which may be substituted or a group represented by the formula ##STR28## or a group represented by the formula ##STR29## (wherein R¹⁹ represents a hydrogen atom, a lower alkyl group, a lower alkoxyalkyl group, an acyl group, a carboxyalkyl group which may be protected or a hydroxyalkyl group; R²⁰, R²¹ and R²², each of which may be the same or different from one another, represent each a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a lower alkyl group, a lower alkoxy group, a lower alkoxyalkyl group, a lower alkenyl group, an acyl group, an acylamino group, an alkylsulfonylamino group, a hydroxyiminoalkyl group, an alkyloxycarbonylamino group, an alkyloxycarbonyloxy group or a heteroaryl group which may be substituted; or, two of R²⁰, R²¹ and R²² may together form a saturated or unsaturated ring which may contain a nitrogen atom, a sulfur atom or an oxygen atom; and r represents 0 or an integer of 1 to 8)].

The present invention also provides a preventive or therapeutic agent for diseases for which phosphodiesterase-inhibiting action is efficacious, especially for which cyclic-GMP phosphodiesterase-inhibiting action is efficacious, which contains a nitrogenous heterocyclic compound or a pharmacologically acceptable salt thereof described above as the active ingredient.

As diseases described above, ischemic heart diseases, concretely angina pectoris, hypertension, heart failure and asthma, are cited.

Furthermore, the present invention provides a drug composition comprising a nitrogenous heterocyclic compound and/or a pharmacologically acceptable salt thereof described above and a pharmacologically acceptable filler.

The present invention provides a use of a nitrogenous heterocyclic compound or a pharmacologically acceptable salt thereof to prepare a therapeutic agent for diseases for which phosphodiesterage-inhibiting action is efficacious, and a treating method for a disease which comprises administering a therapeutic effective amount of a nitrogenous heterocyclic compound and/or a pharmacologically acceptable salt thereof to a patient suffering from a disease for which phosphodiesterase-inhibiting action is efficacious.

The lower alkyl group defined with respect to R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R⁴⁵, R⁴⁶, R⁴⁸, R⁴⁹ and R⁵⁰ in the above definition of the compound (1) according to the present invention is a straight-chain or branched alkyl group having 1 to 8 carbon atoms and examples thereof include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group (amyl group), neopentyl group, tert-pentyl group, 2-methylbutyl group, 3-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, heptyl group and octyl group. Among these groups, methyl group, ethyl group, propyl group and isopropyl group are cited as preferable ones. Among these groups, methyl group and ethyl group are cited as still preferable ones.

In these lower alkyl groups, a carbon atom at its terminal may be represented by a sulfonic acid group (--SO₃ H) or a group represented by the formula --ONO₂. Furthermore, the sulfonic acid group may form a salt such as groups represented by the formulas --SO₃ Na and --SO₃ K.

The lower alkyl group which may be substituted with a halogen atom used in the definition of R¹, R², R³ and R⁴ refers to a lower alkyl group described above in which one or two or more hydrogen atoms may be replaced by halogen atom(s).

The lower alkoxy group defined with respect to R¹, R², R³, R⁴, R⁵, R⁶, R¹³, R¹⁴, R¹⁵, R¹⁶, R²⁰, R²¹, R²², R²³, R⁴⁸, R⁴⁹ and R⁵⁰ is a straight-chain or branched alkoxy group having 1 to 8 carbon atoms and examples thereof include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, 2-methylbutoxy group, 2,3-dimethylbutoxy group and hexyloxy group. Among these groups, methoxy group and ethoxy group are cited as preferable ones.

The lower alkenyl group defined with respect to R⁵, R⁶, R²⁰, R²¹ and R²² is one derived from the above-mentioned lower alkyl group and examples thereof include ethylene group, propylene group, butylene group and isobutylene group.

The hydroxyalkyl group defined with respect to R¹, R², R³, R⁴, R⁵, R¹¹, R¹², R¹⁷, R¹⁹, R²³ and R⁵⁰ is one derived from the above-mentioned lower alkyl group.

The hydroxyalkyl group which may be protected used in the definition of R⁹ refers to a hydroxyalkyl group wherein the hydroxyl group is protected with, for example, nitro group, a lower alkyl group as described above such as methyl group and ethyl group, an acyl group such as acetyl group, propionyl group, butyroyl group, pivaloyl group and nicotinoyl group or other group which may have a c-GMP PDE-inhibitory activity. The nitrogenous heterocyclic compound thus protected according to the present invention exhibits an effect as a drug after being deprotected the protective group in vivo or as such.

The acyl group defined with respect to R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² is one derived from an aliphatic one, an aromatic one or a heterocycle and examples thereof include lower alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group, valeryl group, isovaleryl group and pivaloyl group; aroyl groups such as benzoyl group, toluoyl group and naphthoyl group; and heteroaroyl groups such as furoyl group, nicotinoyl group and isonicotinoyl group. Among these groups, formyl group, acetyl group and benzoyl group are cited as preferable ones.

The carboxyl-protective group defined with respect to R¹, R², R³, R⁴, R⁵, R¹⁸ and R⁵⁰ includes lower alkyl groups such as methyl group, ethyl group and t-butyl group; lower alkyl groups substituted with a phenyl group which may have a substituent, such as p-methoxybenzyl group, p-nitrobenzyl group, 3,4-dimethoxybenzyl group, diphenylmethyl group, trityl group and phenethyl group; halogenated lower alkyl groups such as 2,2,2-trichloroethyl group and 2-iodoethyl group; lower alkanoyloxy lower alkyl groups such as pivaloyloxymethyl group, acetoxymethyl group, propionyloxymethyl group, butyryloxymethyl group, valeryloxymethyl group, 1-acetoxyethyl group, 2-acetoxyethyl group, 1-pivaloyloxyethyl group and 2-pivaloyloxyethyl group; higher alkanoyloxy lower alkyl groups such as palmitoyloxyethyl group, heptadecanoyloxymethyl group and 1-palmitoyloxyethyl group; lower alkoxy-carbonyloxy lower alkyl groups such as methoxycarbonyloxymethyl group, 1-butoxycarbonyloxyethyl group and 1-(isopropoxycarbonyloxy)ethyl group; carboxy lower alkyl groups such as carboxymethyl group and 2-carboxyethyl group; heterocyclic groups such as 3-phthalidyl group; benzoyloxy lower alkyl groups which may have a substituent, such as 4-glycyloxybenzoyloxymethyl group and 4-[N-(t-butoxycarbonyl)glycyloxy]benzoyloxymethyl group; (substituted dioxolene) lower alkyl groups such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group; cycloalkyl-substituted lower alkanoyloxy lower alkyl groups such as 1-cyclohexylacetyloxyethyl group; and cycloalkyloxycarbonyloxy lower alkyl groups such as 1-cyclohexyloxycarbonyloxyethyl group.

Further, the protected carboxyl group also includes various acid amides groups. That is, the protected carboxyl group may be any one, so far as it can be deprotected in vivo to give a carboxyl group. The nitrogenous heterocyclic compound thus protected according to the present invention exhibits an effect as a drug after being deprotected the protective group in vivo or as such.

Although the cycloalkyl group which may be substituted used in the definition of R¹, R², R³, R⁴, R⁵ and R¹⁸ refers to one having 3 to 8 carbon atoms, those having 8 to 6 carbon atoms are preferable.

The heteroaryl group constituting the heteroaryl group which may be substituted defined with respect to R⁵, R¹⁸, R²⁰, R²¹ and R²² is a 5- to 7-membered monocyclic group or a condensed heterocyclic group each containing one to two oxygen atom(s), nitrogen atom(s) or sulfur atom(s) as the heteroatom(s) and examples thereof include furyl group, pyridyl group, thienyl group, imidazolyl group, quinazolyl group and benzimidazolyl group.

The heteroaryl group constituting the heteroarylalkyl group which may be substituted defined with respect to R¹¹ and R¹² refers to any of the heteroaryl groups described above. Further, the alkyl group constituting the heteroaryl group refers to any of the lower alkyl groups described above.

"R¹¹(45) and R¹²(46) and the nitrogen atom to which both groups are bonded may together form a ring which may contain another nitrogen atom or an oxygen atom" described in the definition of R¹¹ and R¹², and R⁴⁵ and R⁴⁶ refers to piperidino group, piperazino group and morpholino group as specific examples. Further, the substituent with which the ring may be substituted includes hydroxyl group; halogen atoms such as chlorine atom, fluorine atom, bromine atom and iodine atom; lower alkyl groups such as methyl, ethyl and t-butyl; lower alkoxy groups such as methoxy, ethoxy and t-butoxy; cyano groups; carboxyl groups which may be protected; hydroxyalkyl groups; carboxyalkyl groups; heteroaryl groups such as tetrazolyl group; and so on. The ring may have one to two substituents described above.

The substituent constituting the "heteroaryl group which may be substituted" contained in the definition of R⁵, R¹⁸, R²⁰, R²¹ and R²², the "phenylalkyloxy group which may be substituted" contained in the definition of R⁶, the "1,3-benzdioxolyl group which may be substituted, 1,4-benzdioxyl group which may be substituted, 1,3-benzdioxolylalkyl group which may be substituted or 1,4-benzdioxylalkyl group which may be substituted" contained in the definition of R⁵, the "benzyl group which may be substituted" defined with respect to R⁹ and the "heteroarylalkyl group which may be substituted" defined with respect to R¹¹ and R¹² includes, for example, hydroxyl group; nitro group; halogen atoms such as chlorine atom, fluorine atom, bromine atom and iodine atom; lower alkyl groups such as methyl, ethyl and t-butyl; lower alkoxy groups such as methoxy, ethoxy and t-butoxy; carboxyl groups which may be protected; hydroxyalkyl groups; carboxyalkyl groups; tetrazolyl group; and so on.

Further, the substituent constituting the "group represented by the formula --(CH₂)_(q) -- wherein each carbon may have one to two substituents when q is an integer of 1 to 8" contained in the definition of Y includes the same substituents as those described above.

Although the acylamino group defined with respect to R¹, R², R³, R⁴, R²⁰, R²¹ and R²² refers to an amino group wherein an acyl group(s) as described above is(are) bonded to the nitrogen atom of the amino group, i.e., monoacylamino group or diacylamino group, the monoacylamino group is preferred.

The halogen atom defined with respect to R¹, R², R³, R⁴, R⁵, R⁶, R²⁰, R²¹, R²² and R⁵⁰ includes fluorine atom, chlorine atom, bromine atom and iodine atom.

The carboxylalkyl group which may be protected defined with respect to R⁵, R⁹, R¹⁰, R¹¹, R¹², R¹⁷ and R¹⁹ is a carboxyalkyl group wherein the carboxyl group may be protected with the carboxyl-protective group described above. Further, the carboxy group(s) in this carboxyalkyl group may be bonded to any and one to two carbon atom(s) of the lower alkyl group as described above.

The carboxyalkenyl group which may be protected defined with respect to R⁵ refers to a carboxyalkenyl group wherein the carboxyl group is protected with the carboxyl-protective group described above. Further, the carboxy group(s) in this carboxyalkenyl group may be bonded to any and one to two carbon atom(s) of the lower alkyl group as described above.

The lower alkoxyalkyl group defined with respect to R¹⁷, R¹⁹, R²⁰, R²¹ and R²² is one derived from the above-mentioned lower alkyl group and examples thereof include methoxymethyl group, methoxyethyl group, methoxybutyl group and ethoxyethyl group.

The aminoalkyl group defined with respect to R¹¹ and R¹² refers to a lower alkyl group as described above wherein an amino group is bonded to any of the carbon atoms constituting the lower alkyl group.

The alkylcarbamoyl group defined with respect to R¹¹ and R¹² refers to one derived from the above-mentioned lower alkyl group.

The carboxyalkylcarbamoyl group which may be protected used in the definition of R¹¹ and R¹² refers to any of the alkylcarbamoyl groups described above which has a carboxyl group, which may be protected, bonded to any carbon atom of the alkyl.

The alkylsulfonylamino group defined with respect to R²⁰, R²¹ and R²² refers to one derived from the above-mentioned lower alkyl group.

The hydroxyiminoalkyl group defined with respect to R²⁰, R²¹ and R²² is a lower alkyl group as described above wherein a hydroxyimino group is bonded to any of the carbon atoms constituting the lower alkyl group.

Although the alkyloxycarbonylamino group defined with respect to R²⁰, R²¹ and R²² is an amino group wherein the nitrogen atom of the amino group is mono- or disubstituted with an alkyloxycarbonyl derived from the above-mentioned lower alkyl group, the mono-substituted alkyloxycarbonylamino group is preferable.

The alkyloxycarbonyloxy group defined with respect to R²⁰, R²¹ and R²² refers to a group wherein an alkyloxycarbonyl derived from the above-mentioned lower alkyl group is bonded to an oxygen atom.

The hydroxyalkyloxy group defined with respect to R²³ refers to one derived from the hydroxyalkyl group described above.

In the compounds of the present invention, a ring part of a bicyclic skeleton wherein the ring A and ring B are combined or a three or more ring skeleton when two of the substituents on the ring A together form a ring, is formed. Among these, desirable examples are as follows: ##STR30##

Among these, a), b), c) and e) are cited as more desirable ones and a), b) and c) are cited as more desirable ones. Most desirable one is a).

The pharmacologically acceptable salt includes inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate; and amino acid salts such as argininate, aspartate and glutamate. Further, some of the compounds may form metal salts such as Na, K, Ca or Mg, and the pharmacologically acceptable salt of the present invention also includes these metal salts.

Although the compound of the present invention may be present as various isomers including geometrical isomers, i.e., cis-isomer and trans-isomer, and optical isomers, i.e., d-isomer and 1-isomer depending upon the kinds and combination of the substituents, it is needless to say that the compounds of the present invention includes all of the isomers.

Preferable specific examples of the compound of the present invention will now be described in order to facilitate the understanding of the present invention, though it is needless to say that the compounds of the present invention are not limited to these examples.

The most desirable specific examples of the compound include compounds represented by the following general formula (A) and pharmacologically acceptable salts thereof: ##STR31## [in general formula (A), R¹, R², R³, R⁴, R¹¹, R¹², R¹⁹, R²⁰, R²¹, R²² and r are the same as those in general formula (1)].

As R¹, R², R³ and R⁴, each of which may be the same or different from one another, hydrogen atom, a halogen atom and cyano group are preferable and, among them, hydrogen atom, cyano group and chlorine atom are still preferable.

To enter into details with respect to the combination of R¹, R², R³ and R⁴, it is desirable that one of R¹, R², R³ and R⁴ is cyano group or chlorine atom and the others are hydrogen atoms and, among them, it is most desirable that R² is cyano group or chlorine atom and R¹, R³ and R⁴ are hydrogen atoms.

As R¹¹ and R¹², each of which may be the same or different from each other, hydrogen atom, a lower alkyl group and a carboxyalkyl group which may be protected are preferable and, among these, hydrogen atom, methyl group and 3-carboxypropyl group are preferable.

Further, it is most desirable that R¹¹ and R¹², together with the nitrogen atom to which they are bonded, form a ring which may be substituted, and among them, a piperidine ring is most desirable. It is still preferable that this ring is substituted with a lower alkyl group, a lower alkoxy group, a carboxyl group which may be protected, a hydroxyl group, a halogen atom, a hydroxyalkyl group or a carboxyalkyl group, and among them, a carboxyl group which may be protected is most preferable.

R¹⁹ is preferably a hydrogen atom or a lower alkyl group such as methyl group and ethyl group, particularly preferably a hydrogen atom.

r is desirably 0, 1 or 2, most desirably 1.

As R²⁰, R²¹ and R²², a hydrogen atom, a lower alkyl group, a lower alkoxy group and a halogen atom are preferable, or it is preferable that two of R²⁰, R²¹ and R²² together form methylenedioxy or ethylenedioxy.

PREPARATION PROCESS

Representative processes for the preparation of the compound according to the present invention will now be described below.

Though compounds having a quinazoline skelton are mainly described in the following explanation, the following explanation can be applied for compounds having a skelton other than the quinazoline skelton.

Preparation Process 1

When R⁵ is a hydrogen atom, a halogen atom or a group selected from among those which are directly bonded to the quinazoline skeleton through a carbon atom in the general formula (I), a compound represented by the general formula (I) can also be prepared by the following process: ##STR32## (in a series of formulas R⁵ _(a) is a hydrogen atom a halogen atom or a group selected from among those which are directly bonded to the quinazoline skeleton through a carbon atom in R⁵ described above; and R¹, R², R³ and R⁴ are each as defined above.

That is, this process is one for preparing a quinazoline derivative represented by the general formula (III) by reacting a quinazoline derivative represented by the general formula (II) with phosphorus oxychloride or by reacting it with phosphorus oxychloride in the presence of phosphorus pentachloride under heating.

Preparation Process 2

When R⁵ is a group selected from among a hydrogen atom, a halogen atom, a group represented by the formula ##STR33## (wherein R⁸ and m are each as defined above), a group represented by the formula --O--R⁹ (wherein R⁹ is as defined above), a heteroaryl group which may be substituted and a group which is directly bonded to the ring through a carbon atom (for example, a lower alkyl group, a carboxyl group which may be protected, a 1,3-benzodioxolyl group which may be substituted, a 1,4-benzodioxyl group which may be substituted, a 1,3-benzodioxolylalkyl group which may be substituted and a 1,4-benzodioxylalkyl group which may be substituted); and R⁶ is a group selected from among those defined above with respect to R⁶ except a hydrogen atom, halogen atoms and lower alkyl groups in the general formula (I), a compound represented by the general formula (I) can be prepared by the following process: ##STR34## [in a series of formulas, R¹, R², R³ and R⁴ are each as defined above; R⁵ _(b) represents a group selected from among a hydrogen atom, a halogen atom, a group represented by the formula ##STR35## (wherein R⁸ and m are each as defined above), a group represented by the formula --O--R⁹ (wherein R⁹ is as defined above), a heteroaryl group which may be substituted and a group which is directly bonded to the ring through a carbon atom (for example, a lower alkyl group, a carboxyl group which may be protected, a 1,3-benzodioxolyl group which may be substituted, a 1,4-benzdioxyl group which may be substituted, a 1,3-benzodioxolylalkyl group which may be substituted and a 1,4-benzodioxylalkyl group which may be substituted); R⁶ _(a) represents a group selected from among those defined above with respect to R⁶ except a hydrogen atom, halogen atoms and lower alkyl groups; and E represents an eliminable group].

That is, this process is one for preparing an objective compound (V) by condensing a quinazoline derivative represented by the general formula (IV) with a compound represented by the general formula (VI).

The eliminable group represented by E in the formula includes halogen atoms and alkoxy groups.

This process may be conducted in the presence of a base at need.

The base includes organic bases such as triethylamine, pyridine and diisopropylethylamine; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydroxide and sodium hydride; and alkoxides such as sodium methoxide and potassium t-butoxide.

As the reaction solvent, every solvent which is inert to the reaction can be used and examples thereof include ethanol, isopropyl alcohol, tetrahydrofuran, dimethylformamide and dimethyl sulfoxide. This process can be conducted even in the absence of any solvent in some cases.

The reaction temperature preferably ranges from -20° to 300° C.

Preparation Process 3

When R⁵ is a group selected from among those defined above with respect to R⁵ except a hydrogen atom, halogen atoms and groups which are directly bonded to the quinazoline skeleton through a carbon atom; and R⁶ is a group selected from among those defined above with respect to R⁶ except halogen atoms in the general formula (I), a compound represented by the general formula (I) can be prepared by the following process: ##STR36## (in a series of formulas, R¹, R², R³ and R⁴ are each as defined above; R⁵ _(c) is a group selected from among those defined above with respect to R⁵ except a hydrogen atom, halogen atoms and groups which are directly bonded to the quinazoline skeleton through a carbon atom;

R⁶ _(b) is a group selected from among those defined above with respect to R⁶ except halogen atoms; and

F represents an eliminable group).

That is, this process is one for preparing an objective compound (VIII) by condensing a compound represented by the general formula (VII) with a compound represented by the general formula (IX).

The eliminable group represented by F in the formula includes, for example, halogen atoms, alkylthio groups and so forth.

This process may be conducted in the presence of a base at need.

The base includes organic bases such as triethylamine, pyridine and diisopropylethylamine; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydroxide and sodium hydride; and alkoxides such as sodium methoxide and potassium t-butoxide.

As the reaction solvent, every solvent which is inert to the reaction can be used and examples thereof include ethanol, isopropanol, tetrahydrofuran, dimethylformamide and dimethyl sulfoxide.

The reaction temperature preferably ranges from 0° to 300° C.

Preparation Process 4

When R⁵ is a group represented by the formula ##STR37## (wherein R²⁴ is a hydrogen atom or a lower alkyl group in the general formula (I), a compound represented by the general Formula (I) can also be prepared by the following process: ##STR38## (in a series of formulas, R¹, R², R³, R⁴ and R⁶ are each as defined above; and R²⁴ and R²⁵, each of which may be the same or different from each other, represent each a hydrogen atom or a lower alkyl group).

That is, this process is one for preparing an objective compound (XI) by reacting a compound represented by the general formula (X) with an ordinary reducing agent or an ordinary nucleophilic reagent, either directly or through the oxidation of an alcohol (XII).

The reducing agent includes lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride and so forth.

The nucleophilic reagent includes lower alkyl metals such as methyllithium, methylmagnesium bromide and so forth.

The oxidizing agent to be used when the reaction is conducted through the alcohol (XII) includes potassium bichromate/sulfuric acid, dimethyl sulfoxide/oxalyl chloride and so forth.

As the reaction solvent, every solvent which is inert to the reaction can be used.

The reaction temperature ranges from 0° C. to the refluxing temperature of the solvent.

Preparation Process 5

When R⁵ is a group represented by the formula ##STR39## (wherein R¹⁰ and R²⁴ are each as defined above) in the general formula (I), a compound represented by the general formula (I) can also be prepared by the following process: ##STR40## (in a series of formulas, R¹, R², R³, R⁴, R⁶, R¹⁰ and R²⁴ are each as defined above).

That is, this process is one for preparing a compound represented by the formula (XIII) by reacting a compound represented by the general formula (XI) with hydroxyamine.

As the reaction solvent, every solvent which is inert to the reaction can be used.

The reaction temperature ranges form 0° C. to the refluxing temperature of the solvent.

Preparation Process 6

When R⁵ is a group represented by the formula ##STR41## (wherein R²⁴ is as defined above; R²⁶ represents a hydrogen atom or a lower alkyl group; and R²⁷ represents a hydrogen atom, a lower alkyl group, a carboxyl group which may be protected or a carboxyalkyl group which may be protected) in the general formula (I), a compound represented by the formula (I) can also be prepared by the following process: ##STR42## (in a series of formulas, R¹, R², R³, R⁴, R⁶, R²⁴, R²⁶ and R²⁷ are each as defined above; and Ph represents a phenyl group).

That is, this process is one for preparing a compound represented by the general formula (XV) by reacting a compound represented by the general formula (XIV) with a compound represented by the general formula (XVI) or the general formula (XVII) through the Wittig reaction.

As the reaction solvent, every solvent which is inert to the reaction can be used.

The reaction temperature ranges from 0° C. to the refluxing temperature of the solvent.

Preparation Process 7

When R⁵ is a group represented by the formula ##STR43## (wherein R²⁴, R²⁶ and R²⁷ are each as defined above) in the general formula (I), a compound represented by the formula (I) can also be prepared by the following process: ##STR44## (in a series of formulas, R¹, R², R³, R⁴, R⁶, R²⁴, R²⁶ and R²⁷ are each as defined above).

That is, this process is one for preparing an objective compound (XVIII) by reducing the compound represented by the general formula (XV) prepared in the Preparation process 6.

The reduction can be conducted by conventional means, for example, catalytic reduction using palladium/carbon or platinum catalyst.

As the reaction solvent, every solvent which is inert to the reaction is used.

Preparation Process 8

When R⁶ is a group represented by the formula ##STR45## (wherein R¹⁹, R²⁰, R²¹ and r are each as defined above) in the general formula (t), a compound represented by the general formula (I) can also be prepared by the following process: ##STR46## (in a series of formulas, R¹, R², R³, R⁴, R⁵, R¹⁹, R²⁰, R²¹ and r are each as defined above).

That is, this process is one for preparing an objective compound (XX) by reducing a compound represented by the general formula (XIX).

The reduction is conducted by conventional means, e.g., catalytic reduction using palladium/carbon or platinum catalyst or reduction with iron or tin.

As the reaction solvent, every solvent which is inert to the reaction can be used.

Preparation Process 9

When R⁵ is a group represented by the formula --O'R^(9') (wherein R^(9') is a carboxyl group which may be protected) in the general formula (I), a compound represented by the formula (I) can be prepared by the following process:

The First Step ##STR47## (in a series of formulas, R¹, R², R³, R⁴ and R⁶ are each as defined above; and m represents 0 or an integer of 1 to 2).

That is, this process is one for preparing a compound represented by the general formula (XXII) by oxidizing a compound represented by the general formula (XXI) by conventional means.

As the oxidizing agent, everyone can be used so far as it is conventionally used and examples thereof include chrominum (VI), dimethyl sulfoxide and oxalyl chloride.

As the reaction solvent, every solvent which is inert to the reaction can be used.

The reaction temperature ranges from 0° C. to the refluxing temperature of the solvent.

The Second Step ##STR48## (in a series of formulas, R¹, R², R³, R⁴, R⁶ and m are each as defined above; and R²⁸, R²⁹ and R³⁰, each of which may be the same or different from one another, represent each a hydrogen atom or a lower alkyl group).

That is, this process is one for preparing a compound represented by the general formula (XXIV) by reacting the compound (XXII) prepared in the first step with the Wittig reagents (XXIII) or (XXIII)'.

As the reaction solvent, everyone which is inert to the reaction can be used.

The reaction temperature ranges from 0° C. to the refluxing temperature of the solvent.

The Third Step ##STR49## (in a series of formulas, R¹, R², R³, R⁴, R⁶, R²⁹, R³⁰ and m are each as defined above).

That is, this process is one for preparing the objective compound (XXV) by reducing the compound (XXIV) prepared in the second step.

The reduction may be conducted by conventional means, and examples thereof include catalytic reduction using palladium/carbon or platinum catalyst.

Preparation Process 10

When R⁶ is a group represented by the formula ##STR50## (wherein R¹⁹, R²⁰, R²¹ and r are each as defined above; and R³¹ represents an acyl group, a lower alkylsulfonyl group or a lower alkyloxycarbonyl group) in the general formula (I), a compound represented by the general formula (I) can also be prepared by the following process: ##STR51## (in a series of formulas, R¹, R², R³, R⁴, R⁵, R¹⁹, R²⁰, R²¹, R³¹ and r are each as defined above).

That is, this process is one for preparing an objective compound (XXVI) by subjecting the compound represented by the general formula (IX) prepared in the Preparative process 8 to the conventional acylation, sulfonylation or alkoxycarbonylation in the presence of a base.

As the acylating agent, every acylating agent which is conventionally used, for example, activated derivatives of carboxylic acids such as acid chloride, acid anhydride and mixed acid anhydride; and condensing agents such as dicyclohexylcarbodiimide is used.

As the sulfonylating agent, every sulfonylating agent which is conventionally used can be used and examples thereof include a lower alkylsulfonyl chloride and a lower alkylsulfonic anhydride.

The alkoxycarbonylating agent includes every alkoxycarbonylating agent which is conventionally used, for example, a lower alkyloxycarbonyl chloride and a lower alkyl pyrocarbonate.

As the base, every base can be used and examples thereof include organic bases such as pyridine and triethylamine; and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide and sodium hydride.

Preparation Process 11

When the ring A is selected from any of a benzene ring, a pyridine ring and a cyclohexane ring, the ring B is selected from among a pyridine ring, a pyrimidine ring and an imidazole ring, R⁵ represents a group selected from among those defined above with respect to R⁵ except groups which are directly bonded to the ring portion through a carbon atom; and R⁶ represents a group selected from among those defined above with respect to R⁵ except groups which are directly bonded to the ring portion through a carbon atom in the general formula (1), the compound represented by the general formula (1) can also be prepared by the following process. The case in which the ring portion forms a quinazoline skeleton is shown below as the representative of the above:

The First Step ##STR52## (in a series of formulas, R¹, R², R³ and R⁴ are each as defined above; R⁵ _(a) represents a group selected from among those defined above with respect to R⁵ except groups which are directly bonded to the ring portion through a carbon atom; and X represents a halogen atom).

That is, the first step is a condensation reaction according to a conventional process.

Alcohol solvents such as isopropyl alcohol, ether solvents such as tetrahydrofuran and dimethylformamide are preferably used as the reaction solvent. However, every solvent which is inert to the reaction can be used.

In the case where R⁵ _(a) is bonded to the ring portion through a nitrogen atom, it is preferred that the reaction is proceeded by heating under reflux in the presence of a tertiary amine such as triethylamine while removing HCl generated. While in the case where R⁵ _(a) is bonded to the ring portion through an oxygen atom or a sulfur atom, it is preferred that the reaction is proceeded by heating under reflux in the presence of an alkali such as sodium hydroxide and sodium carbonate.

The Second Step ##STR53## (in a series of formulas R¹, R², R³, R⁴, R⁵ _(a) and X are each as defined above; R⁶ _(a) represents a group selected from among those defined above with respect to R⁶ except groups which are directly bonded to the ring portion through a carbon atom).

The second step is a reaction wherein the compound (XXVIII) obtained in the first step is condensed with a compound represented by the formula R⁶ _(a) --H according to a conventional process

Alcohol solvents such as isopropyl alcohol, ether solvents such as tetrahydrofuran and dimethylformamide are preferably used as the reaction solvent. However, every solvent which is inert to the reaction can be used.

In the case where R⁶ _(a) is bonded to the ring portion through a nitrogen atom, it is preferred that the reaction is proceeded by heating under reflux in the presence of an organic base such as triethylamine, pyridine and ethyldiisopropylamine, an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydride and sodium hydroxide or an alkoxide such as sodium methoxide and potassium t-butoxide. While in the case where R⁶ _(a) is bonded to the ring portion through an oxygen atom or a sulfur atom, it is preferred that the reaction is proceeded by heating under reflux in the presence of an alkali such as sodium hydroxide and sodium carbonate.

Preparation Process 12

When the compound represented by the general formula (1) is a compound represented by the following general formula (XXXII): ##STR54## the compound can also be prepared by the following process. ##STR55## (in a series of formulas, R¹, R², R³, R⁴ and R⁵ are each as defined above; and R⁶ _(b) represents a group selected from among groups which are directly bonded to the ring portion through a carbon atom in those defined above with respect to R⁶).

That is, this process is one for preparing an objective compound by reacting, for example, piperonyl chloride (XXXI) with a benzimidazole derivative represented by the general formula (XXX) in the presence of an alkali by a conventional process.

Sodium iodide is preferred as alkali.

Although every solvent which is inert to the reaction can be used as the reaction solvent, polar solvents such as dimethylformamide can be cited as preferable ones.

The reaction temperature is preferably about 60° to 100° C., particularly preferably about 70° to 80° C.

Preparation Process 13

The compound of the present invention can also be prepared by the following process:

The First Step ##STR56## (in a series of formulas, R¹, R², R³ and R⁴ are each as defined above; R⁶ _(d) represents a group selected from among those defined above with respect to R⁶ except groups which are directly bonded to the ring portion through a carbon atom; and Q and Q' represent halogen atoms).

The first step is a condensation reaction according to a conventional process.

In the case where R⁶ _(d) is bonded to the ring portion through a nitrogen atom, it is preferred that the reaction is proceeded by heating under reflux in the presence of an organic base such as triethylamine, pyridine and diisopropylethylamine, an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydroxide and sodium hydride or an alkoxide such as sodium methoxide and potassium t-butoxide. While in the case where R⁶ _(d) is bonded to the ring portion through an oxygen atom or a sulfur atom, it is preferred that the reaction is proceeded by heating under reflux in the presence of an inorganic base such as sodium hydroxide and sodium carbonate.

Every solvent which is inert to the reaction can be used as the reaction solvent, and examples thereof include alcohol solvents such as ethanol and isopropyl alcohol, ether solvents such as tetrahydrofuran, dimethylformamide and dimethylsulfoxide. Further, in the present process, the reaction can be proceeded in the absence of a reaction solvent in some cases.

The Second Step ##STR57## (in a series of formulas, R¹, R², R³, R⁴, R⁶ _(d) and Q are each as defined above; and R⁵ _(d) represents a group selected from among those defined above with respect to R⁵ except groups which are directly bonded to the ring portion through a carbon atom).

That is, the second step is a process for preparing an objective compound in which the compound obtained in the first step is condensed with a compound represented by the general formula R⁵ _(d) --H.

In the present process, the reaction can be proceeded in the presence of a base at neeed.

As the base, organic bases such as triethylamine, pyridine and diisopropylethylamine, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydroxide and sodium hydride and alkoxides such as sodium methoxide and potassium t-butoxide can be cited.

Every solvent which inert to the reaction can be used as the reaction solvent, and examples thereof include alcohol solvents such as ethanol and isopropanol, ether solvents such as tetrahydrofuran, dimethylformamide and dimethylsulfoxide.

The reaction temperature is preferably 0° C. to 300° C.

In the case where R⁵ _(d) is a group which is bonded to the ring portion through a nitrogen atom, it is preferred that the reaction is proceeded by heating under reflux in the presence of a tertiary amine such as triethylamine. While in the case where R⁵ _(d) is a group which is bonded to the ring portion through an oxygen atom or a sulfur atom, it is preferred that the reaction is proceeded by heating under reflux in the presence of an alkali such as sodium hydroxide and sodium carbonate.

The compounds thus obtained in the preparation processes 1 to 13 described above can form salts thereof by a conventional process, for example, by adding sodium hydroxide, potassium hydroxide or methanesulfonic chloride.

Next, the preparation processes for the raw compounds used in the preparation processes will be shown.

Preparation Process A

Among the starting materials used in the preparation process 13, the compound in which the ring portion is a quinazoline ring and Q and Q' are chlorine atoms can also be prepared by the following process: ##STR58## (in a series of formulas, R¹, R², R³ and R⁴ are each as defined above; and X' represents any group among a hydroxyl group, an alkoxy group and an amino group).

That is, this process is one for preparing the objective compound (c) by cyclizing the compound (a) by a conventional process to obtain the compound (b) and then chlorinating it by a conventional process.

The first step is a cyclization reaction. It is a step in which urea is reacted with the compound (a) to obtain the compound (b). In this case, the reaction temperature is preferably about 170° to 190° C., and although every solvent can be used as long as it is inert to the reaction, preferable examples thereof include N-methylpyrrolidone and the like. In this step, the reaction can also be proceeded in the absence of the solvent.

Further, the compound (b) can also be obtained by cyclizing with carbonyldiimidazole or by cyclizing under an acidic or basic condition after converting to urethane with a chloroformic ester when X' is an amino group.

The second step is a chlorination reaction. This step can be carried out by a conventional manner, and examples thereof include a process in which the compound (b) is heated under reflux with phosphorus pentachloride and phosphorus oxychloride, or phosphorus oxychloride while stirring to chlorinate.

Preparation Process B

The starting material (II) used in the preparation process 1 can be prepared by the following process: ##STR59## (in a series of formulas, R¹, R², R³ and R⁴ are each as defined above; and R⁵ _(c) represents a halogen atom or a group selected from among groups which are directly bonded to the ring portion through a carbon atom in those defined with respect to above R⁵).

That is, the above process is a reaction in which an amide product is obtained by a conventional process in the first step and a cyclization is carried out in the presence of an acid or a base in the second step.

The amide product (e) can be obtained by a conventional process, and it can be obtained, for example, by reacting the compound (d) with an acylating agent such as an acid chloride represented by R⁵ _(c) --COCl in the presence of a base

Tertiary amines such as triethylamine and organic bases such as pyridine are preferably cited as the base.

Specific examples of the acylating agent include acid chlorides such as benzoyl chloride, acetyl chloride, ethyloxalyl chloride and benzyloxyacetyl chloride.

The reaction temperature is preferably about 0° C. to 30° C.

In the second step, the compound (e) obtained in the first step is heated under reflux in the presence of an acid or a base to obtain the compound (f).

The acid includes acetic anhydride and the like.

The base includes sodium hydroxide and the like.

Preparation Process C

The starting material (II) can also be prepared by the following process when R⁵ _(a) is a hydrogen atom in the preparation process 1: ##STR60## (in a series of formulas, R¹, R², R³ and R⁴ are each as defined above; and X" represents a hydroxyl group or a lower alkoxy group).

That is, the above process is a cyclization reaction by a conventional process.

The objective compound (h) can be synthesized, for example, by condensing the raw compound (g) with formamide by heating under reflux, or by heating it together with formic acid.

EFFECT OF THE INVENTION

Experimental Examples will now be described to illustrate the effect of the compound of the present invention.

Experimental Examples Enzyme Inhibiting Action with the Use of cGMP-PDE Prepared from the Swine Aeorta

1. Method of Experiment

The enzymatic activity of the cGMF-PDE prepared from the swine aeorta was determined according to the method of Thompson et al..sup.(1) The enzymatic activity thereof was determined in the presence of 1 mM EGTA by the use of 1 μM cGMP as a substrate. The compound of the present invention was dissolved in DMSO, added to the reaction liquid and examined for the inhibitory activity. The final concentration of DMSO in the reaction liquid was adjusted to 4% or below.

Preparation of cGMP-PDE

The swine aeorta was sliced, followed by the addition of 10 times by volume as much Buffer A (20 mM Tris/HCl, 2 mM Mg acetate, 1 mM Dithiothreitol, 5 mM EDTA, 1400 TIU/liter aprotinin, 10 mg/liter leupeptin, 1 mM benzamidine, 0.2 mM PMSF, pH 7.5). The obtained mixture was homogenized and the homogenate was centrifuged at 100000×g for one hour. The obtained supernatant was supplied a DEAE-Toyopearl 650S (Tosoh, Tokyo, Japan) column. After the column was washed with Buffer B (50 mM Tris/HCl, 0.1 mM EGTA, 2 mM Mg acetate, 1 mM Dithiothreitol, 0.2 mM PMSF, pH 7.5), gradient elution with 0.05 to 0.4M NaCl was conducted. Thus, CaM-independent cGMP-PDE fractions were obtained.

2. Results of Experiment

The results of experiment of the compounds of the present invention are given in Tables 1 to 6B.

                  TABLE 1                                                          ______________________________________                                                Ex. No.                                                                               IC.sub.50 (μM)                                                ______________________________________                                                 7     1.0                                                                     19     0.39                                                                    22     0.36                                                                    25     0.78                                                                    33     0.37                                                                    38     0.42                                                                    40     0.65                                                                    41     0.35                                                                    42     0.19                                                                    45     0.41                                                                    46     0.24                                                                    49     0.041                                                                   50     0.032                                                                   51     0.069                                                                   52     0.069                                                                   53     0.12                                                                    54     0.47                                                                    55     0.030                                                                   57     0.038                                                                   58     0.042                                                                   59     0.27                                                                    60     0.18                                                                    61     0.42                                                             ______________________________________                                    

                  TABLE 2                                                          ______________________________________                                                Ex. No.                                                                               IC.sub.50 (μM)                                                ______________________________________                                                64     0.38                                                                    65     0.093                                                                   67     0.14                                                                    68     0.62                                                                    69     0.19                                                                    70     0.84                                                                    71     0.81                                                                    72     0.73                                                                    73     0.94                                                                    74     0.35                                                                    78     0.50                                                                    81     0.44                                                                    82     0.55                                                                    83     0.024                                                                   84     0.22                                                                    86     0.96                                                                    87     0.68                                                                    89     0.16                                                                    91     0.036                                                                   92     0.094                                                                   93     0.032                                                                   95     0.20                                                                    97     0.79                                                             ______________________________________                                    

                  TABLE 3                                                          ______________________________________                                                Ex. No.                                                                               IC.sub.50 (μM)                                                ______________________________________                                                 98    0.062                                                                   104    0.010                                                                   105    0.18                                                                    107    0.0040                                                                  114    0.0030                                                                  112    0.0020                                                                  115    0.0020                                                                  120    0.0010                                                                  121    0.65                                                                    122    0.0050                                                                  123    0.031                                                                   124    0.0080                                                                  125    0.0090                                                                  126    0.0010                                                                  127    0.11                                                                    128    0.30                                                                    133    0.77                                                                    134    0.0050                                                                  136    0.93                                                                    137    0.38                                                                    138    0.81                                                                    139    0.021                                                                   140    0.68                                                             ______________________________________                                    

                  TABLE 4                                                          ______________________________________                                                Ex. No.                                                                               IC.sub.50 (μM)                                                ______________________________________                                                146    0.015                                                                   150    0.0072                                                                  151    0.081                                                                   152    0.11                                                                    164    0.0080                                                                  165    0.016                                                                   166    0.026                                                                   167    0.56                                                                    168    0.011                                                                   169    0.011                                                                   170    0.029                                                                   171    0.00040                                                                 172    0.095                                                                   174    0.0040                                                                  175    0.0060                                                                  176    0.0030                                                                  177    0.012                                                                   178    0.011                                                                   179    0.0020                                                                  180    0.0090                                                                  181    0.0050                                                                  182    0.0080                                                                  183    0.00040                                                          ______________________________________                                    

                  TABLE 5                                                          ______________________________________                                                Ex. No.                                                                               IC.sub.50 (μM)                                                ______________________________________                                                184    0.0060                                                                  185    0.010                                                                   187    0.12                                                                    188    0.029                                                                   189    0.016                                                                   190    0.0050                                                                  191    0.019                                                                   192    0.020                                                                   193    0.00080                                                                 194    0.0040                                                                  197    0.066                                                                   200    0.064                                                                   201    0.049                                                                   202    0.0020                                                                  203    0.028                                                                   204    0.0040                                                                  206    0.029                                                                   208    0.00019                                                                 213    0.023                                                                   214    0.0090                                                                  216    0.017                                                                   220    0.00024                                                                 222    0.0065                                                           ______________________________________                                    

                  TABLE 6A                                                         ______________________________________                                                Ex. No.                                                                               IC.sub.50 (μM)                                                ______________________________________                                                227    0.0026                                                                  228    0.00052                                                                 230    0.0058                                                                  231    0.41                                                                    232    0.044                                                                   233    0.013                                                                   234    0.0060                                                                  235    0.0020                                                                  236    0.0060                                                                  237    0.014                                                                   238    0.0050                                                                  239    0.0080                                                                  240    0.0040                                                                  241    0.18                                                                    243    0.00015                                                                 244    0.0090                                                                  245    0.10                                                             ______________________________________                                    

                  TABLE 6B                                                         ______________________________________                                                Ex. No.                                                                               IC.sub.50 (μM)                                                ______________________________________                                                255    0.032                                                                   256    0.0021                                                                  260    0.00016                                                                 262    0.88                                                                    266    0.11                                                                    278    0.25                                                                    280    0.25                                                                    376    0.021                                                            ______________________________________                                    

It became apparent from the above experimental examples that the compounds of the present invention exhibit PDE, particularly cGMP-PDE, inhibiting action. That is, it became obvious that the compounds of the present invention exhibit the effect to increase the concentration of cGMP in vivo by revealing the cGMP-PDE inhibiting action. Accordingly, the nitrogenous heterocyclic compounds which are the compounds of the present invention are effective in the prevention and medical treatment of diseases for which cGMP-PDE inhibiting action is efficacious. Examples of these diseases include ischemic heart disease such as angina pectoris, myocardial infarction and chronic and acute cardiac failures, lung hypertension which may accompany with cor pulmonale, other hypertensions attributable to all causes, peripheral circulatory disturbance, brain circulatory diturbance, brain function diturbance and allergic diseases such as bronchial asthma, atopic dermatitis and allergic rhinitis.

Those inhibiting a calmodulin-depending type PDE are also included in the compound group of the present invention. There is high possibility that the diseases for which this action is efficacious are the same as the diseases for which cGMP-PDE inhibitoy action described above is efficacious, and, also from this point, it can be said that the compounds of the present invention can be used for prevention and medical treatment of the diseases described above.

Further, the compounds of the present invention are lowly toxic and therefore are extremely safe. Therefore, the present invention is valuable also from this standpoint.

When the compounds of the present invention are used as drugs for these diseases, they may be each administered orally or parenterally. The dose varies depending upon the extent of symptom; age, sex, weight and sensitivity of a patient; the method of administration; the timing and interval of administration, the properties, dispensing and kind of medical preparation; and the kind of an active ingredient and is not particularly limited.

In orally administration, the dose thereof per adult a day is generally about 1 to 1000 mg, preferably about 5 to 500 mg, still preferably 10 to 100 mg, which may be generally administered in 1 to 3 portions a day.

In the case of an injection, the dose thereof is generally 1 μg/kg to 3,000 μg/kg, preferably about 3 μg/kg to 1,000 μg/kg.

In the preparation of a solid preparation for oral administration, a filler and, if necessary, a binder, disintegrator, lubricant, color and/or corrigent is(are) added to the active ingredient and then there is shaped into a tablet, a coated tablet, granule, powder or a capsule by a conventional manner.

Examples of the filler to be used include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide; those of the binder to be used include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin; those of the lubricant to be used include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oil; those of the color to be used include those authorized as pharmaceutical additives; and those of the corrigent to be used include cocoa powder, mentha herb, aromatic acid, mentha oil, borneol and powdered cinnamon bark. Of course, the tablet and granule may be suitably coated with sugar, gelatin or the like, if necessary.

In the preparation of an injection, a pH modifier, buffer, suspending agent, solubilizing agent, stabilizer, tonicity agent and/or preservative is(are) added to the active ingredient at need and then there is formulated into an injection for intravenous, subcutaneous or intramuscular administration by a conventional manner. It is also necessary that the injection is freeze-dried according to a conventional method.

Examples of the suspending agent include methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, tragacanth powder, sodium carboxymethylcellulose and polyoxyethylene sorbitan monolaurate.

Examples of the solubilizing agent include polyoxyethylene hardened castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol and ethyl ester of castor oil fatty acid.

Example

Examples of the present invention will now be described, though it is needless to say that the present invention is not limited to them. In advance of Examples, preparative example of the raw compound for compounds according to the present invention will be described. In the Examples, Me represents a methyl group, Et an ethyl group, Bzl a benzyl group and Ac an acetyl group.

Preparative Example 1 2-Ethoxycarbonyl-6-chloroquinazolin-4(3H)-one ##STR61##

2.50 g (0.0147 mol) of 2-amino-5-chlorobenzamide was dissolved in 15 ml of pyridine. 2.0 ml of ethyloxalyl chloride was dropped into the obtained solution under stirring at room temperature. The obtained mixture was stirred for several hours and distilled under a reduced pressure to remove the solvent. The obtained residue was used as such in the subsequent reaction.

The residue was dissolved in 50 ml of acetic acid, followed by the addition of 5 ml of acetic anhydride. The obtained mixture was heated under reflux for 24 hours. The solvent was distilled away under a reduced pressure and ethanol was added to the obtained crystalline residue. The obtained mixture was filtered to recover the crystal. The crystal was washed with ethanol and ether and air-dried to give 2.78 g of the title compound as a pale-yellow crystal.

yield (%); 75

m.p. (°C.); 239˜240

Mass; 253 (M+H)⁺

NMR δ (DMSO-d₆); 1.36 (3H, t, J=7.2Hz), 4.39 (2H, q, J=7.2Hz), 7.86 (1H, d, J=8.8Hz), 7.92 (1H, dd, J=8.8Hz, 2.4Hz), 8.11 (1H, d, J=2.4Hz), 12.85 (1H, brs)

Example 1 4-Chloro-6-cyanoquinazoline ##STR62##

A mixture comprising 2 g of 4-hydroxy-6-carbamoylquinazoline, 30 ml of thionyl chloride and 60 ml of phosphorus oxychloride was heated under reflux for 20 hours. The reaction mixture was concentrated under a reduced pressure and the obtained residue was dissolved in 100 ml of ethyl acetate. The obtained solution was washed with water (150 ml), dried over magnesium sulfate and concentrated under a reduced pressure. The obtained residue was introduced into a silica gel column, followed by eluting with ethyl acetate and acetone to give 800 mg of the title compound.

molecular formula; C₃ H₄ N₃ Cl (189.5)

yield (%); 40

m.p. (°C.); >290

Mass; 190 (M+1)⁺

NMR δ (DMSO-d₆); 7.79 (1H, d, J=8.8Hz), 8.16 (1H, dd, J=8.8Hz, 2.0Hz), 8.26 (1H, s), 8.49 (1H, d, J=2.0Hz)

Example 2 2,4-Dichloro-6-cyanoquinazoline ##STR63##

12 g of 2,4-dihydroxy-6-carbamoylquinazoline and 48.8 g of phosphorus pentachloride were suspended in a mixture comprising 200 ml of phosphorus oxychloride and 70 ml of thionyl chloride and the obtained suspension was heated under reflux for 24 hours. The reaction mixture was concentrated under a reduced pressure and the obtained crystalline residue was washed with 100 ml of ethyl acetate and 100 ml of n-hexane to give 6.8 g of the title compound.

molecular formula; C₃ H₃ Cl₂ N₃

yield (%); 52

m.p. (°C.); 161˜163

Mass; 224 (M+1)⁺

NMR δ (CDCl₃); 7.94 (1H, d, J=8.0Hz), 8.00 (1H, dd, J=8.0Hz, 2.0Hz), 8.49 ((1H, d, J=2.0Hz)

Example 3 2-Ethoxycarbonyl-4,6-dichloroquinazoline ##STR64##

2.68 g (0.0106 mol) of 2-ethoxycarbonyl-6-chloroquinazolin-4(3H)-one obtained in Preparative Example 1 was suspended in 40 ml of phosphorus oxychloride. The suspension was heated under reflux for one hour and distilled under a reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate and the obtained solution was washed with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was recovered, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent, giving 2.82 g of the title compound as a pale-yellow crystal.

yield (%); 98

m.p. (°C.); 129˜130

Mass; 271 (M+1)⁺

NMR δ (CDCl₃); 1.50 (3H, t, J=7.2Hz), 4.60 (2H, q, J=7.2Hz), 7.99 (1H, dd, J=8.8Hz, 2.4Hz), 8.25 (1H, d, J=8.8Hz), 8,34 (1H, d, J=2.4Hz)

Example 4 4-(3,4-Methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR65##

21.2 g (0.083 mol) of 4-chloro-6,7,8-trimethoxyquinazoline, 17.0 g (0.112 mol) of piperonylamine and 13.5 g (0.127 mol) of sodium carbonate were mixed with 400 ml of isopropyl alcohol. The obtained mixture was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate to give 21.3 g of the title compound as a pale-yellow needle.

molecular formula; C₁₉ H₁₉ N₃ O₅

yield (%); 69

m.p. (°C.); 197˜198

Mass; 370 (M+H)⁺

NMR δ (CDCl₃); 3.94 (3H, s), 4.03 (3H, s), 4.12 (3H, s), 4.76 (2H, d, J=8.0Hz), 5.55 (1H, brs), 5.97 (2H, s), 6.64 (1H, s), 6.80 (1H, d, J=8.0Hz), 6.87 (1H, d, J=8.0Hz), 6.91 (1H, s), 8.66 (1H, s)

Examples 5 to 4

The following compounds were prepared in a similar manner to that of Example 4.

Example 5 4-(3,4-Methylenedioxyphenyl)amino-6,7,8-trimethoxyquinazoline ##STR66##

molecular formula; C₁₈ H₁₇ N₃ O₅

yield (%); 58

m.p. (°C.); 254˜255 (dec.)

Mass; 356 (M+H )⁺

NMR δ (CDCl₃); 4.02 (3H, s), 4.05 (3H, s), 4.13 (3H, s), 5.99 (2H, s), 6.83 (1H, d, J=7.6Hz), 7.02 (1H, d, J=7.6Hz), 7.32 (1H, s), 7.33 (1H, s), 8.49 (1H, brs), 8.63 (1H, s)

Example 6 4-Benzylamino-6,7,8-trimethoxyquinazoline ##STR67##

molecular formula; C₁₈ H₁₉ N₃ O₃

yield (%); 91

m.p. (°C.); 180˜181

Mass; 326 (M+H)⁺

NMR δ (CDCl₃); 3.94 (3H, s), 4.03 (3H, s), 4.13 (3H, s), 4.87 (2H, d, J=5.2Hz), 5.62 (1H, brs), 6.65 (1H, s), 7.4 (5H, m), 8.67 (1H, s)

Example 7 4-(4-Methoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR68##

molecular formula; C₁₉ H₂₁ N₃ O₄

yield (%); 97

m.p. (°C.); 174˜175

Mass; 356 (M+H)⁺

NMR δ (CDCl₃); 3.82 (3H, s), 3.93 (3H, s), 4.03 (3H, s), 4.13 (3H, s), 4.79 (2H, d, J=4.8Hz), 5.53 (1H, brs), 6.63 (1H, s), 6.92 (2H, d, J=8.4Hz), 7.35 (2H, d, J=8.4Hz), 8.67 (1H, s)

Example 8 4-(3-Methoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR69##

molecular formula; C₁₉ H₂₁ N₃ O₄

yield (%); 89

m.p. (°C.); 142˜143

Mass; 356 (M+H)⁺

NMR δ (CDCl₃); 3.80 (3H, s), 3.96 (3H, s), 4.03 (3H, s), 4.12 (3H, s), 4.85 (2H, d, J=4.8Hz), 5.96 (1H, brs), 6.76 (1H, s), 6.86 (1H, d, J=8.0Hz), 6.99 (1H, d, J=8.0Hz), 7.02 (1H, s), 7.29 (1H, t, J=8.0Hz), 8.65 (1H, s)

Example 9 4-(4-Nitrobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR70##

molecular formula; C₁₈ H₁₈ N₄ O₅

yield (%); 28

m.p. (°C.); 210˜212

Mass; 371 (M+H)⁺

NMR δ (CDCl₃); 3.97 (3H, s), 4.05 (3H, s), 4.13 (3H, s), 5.01 (2H, d, J=5.6Hz), 5.96 (1H, brs), 6.76 (1H, s), 7.54 (2H, d, J=8.8Hz), 8.17 (2H, d, J=8.8Hz), 8.62 (1H, s)

Example 10 4-(3-Nitrobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR71##

molecular formula; C₁₈ H₁₈ N₄ O₅

yield (%); 30

m.p. (°C.); 159˜160

Mass; 371 (M+H)⁺

NMR δ (CDCl₃); 3.97 (3H, s), 4.04 (3H, s), 4.12 (3H, s), 4.99 (2H, d, J=5.6Hz), 6.06 (1H, brs), 6.79 (1H, s), 7.51 (1H, t, J=8.0Hz), 7.76 (1H, d, J=8.0Hz), 8.12 (1H, d, J=8.0Hz), 8.22 (1H, s), 8.63 (1H, s)

Example 11 4-(4-Chlorobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR72##

molecular formula; C₁₈ H₁₈ N₃ O₃ Cl

yield (%); 61

m.p. (°C.); 181˜182

Mass; 860 (M+H)⁺

NMR δ (CDCl₃); 3.94 (3H, s), 4.03 (3H, s), 4.12 (3H, s), 4.85 (2H, d, J=5.6Hz), 5.76 (1H, brs), 6.70 (1H, s), 7.32 (4H, brs), 8.64 (1H, s)

Example 12 4-(3-Chlorobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR73##

molecular formula; C₁₈ H₁₈ N₃ O₃ Cl

yield (%); 85

m.p. (°C.); 161˜162

Mass; 360 (M+H)⁺

NMR δ (CDCl₃); 3.97 (3H, s), 4.04 (3H, s), 4.13 (3H, s), 4.87 (2H, d, J=5.2Hz), 5.66 (1H, brs), 6.68 (1H, s), 7.29 (3H, s), 7.39 (1H, s), 8.65 (1H, s)

Example 13 4-Furfurylamino-6,7,8-trimethoxyquinazoline ##STR74##

molecular formula; C₁₆ H₁₇ N₃ O₄

yield (%); 81

m.p. (°C.); 198˜199

Mass; 316 (M+H)⁺

NMR δ (CDCl₃); 3.97 (3H, s), 4.03 (3H, s), 4.12 (3H, s), 4.87 (2H, d, J=5.2Hz), 5.67 (1H, brs), 6.37 (2H, m), 6.68 (1H, s), 7.42 (1H, s), 8.67 (1H, s)

Example 14 4-(4-Picolyl)amino-6,7,8-trimethoxyquinazoline ##STR75##

molecular formula; C₁₇ H₁₈ N₄ O₃

yield (%); 76

m.p. (°C.); 166˜168

Mass; 327 (M+H)⁺

NMR δ (CDCl₃); 3.97 (3H, s), 4.05 (3H, s), 4.12 (3H, s), 4.92 (2H, d, J=6.0Hz), 6.06 (1H, brs), 6.80 (1H, s), 7.28 (2H, d, J=6.0Hz), 8.55 (2H, d, J=6.0Hz), 8.62 (1H, s)

Example 15 4-(4-Ethylbenzyl)amino-6,7,8-trimethoxyquinaziline ##STR76##

molecular formula; C₂₀ H₂₃ N₃ O₃

yield (%); 88

m.p. (°C.); 195˜196

Mass; 354 (M+H)⁺

NMR δ (CDCl₃); 1.25 (3H, t, J=7.6Hz), 2.67 (2H, q, J=7.6Hz), 3.94 (3H, s), 4.03 (3H, s), 4.13 (3H, s), 4.83 (2H, d, J=4.8Hz), 5.56 (1H, brs), 6.63 (1H, s), 7.23 (2H, d, J=8.0Hz), 7.35 (2H, d, J=8.0Hz), 8.67 (1H, s)

Example 16 4-(Indan-5-ylmethyl)amino-6,7,8-trimethoxyquinazoline ##STR77##

molecular formula; C₂₁ H₂₃ N₃ O₃

yield (%); 61

m.p. (°C.); 198˜199

Mass; 366 (M+H)⁺

NMR δ (CDCl₃); 2.11 (2H, quintet, J=7.2Hz), 2.93 (4H, t, J=7.2Hz), 3.94 (3H, s), 4.04 (3H, s), 4.14 (3H, s), 4.83 (2H, d, J=4.4Hz), 5.55 (1H, brs), 6.64 (1H, s), 7.2˜7.3 (3H, m), 8.68 (1H, s)

Example 17 4-(4-Carboxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR78##

molecular formula; C₁₉ H₁₉ N₃ O₅

yield (%); 86

m.p. (°C.); 227˜228 (dec.)

Mass; 370 (M+H)⁺

NMR δ (DMSO-d₆); 3.89 (3H, s), 3.92 (3H, s), 3.98 (3H, s), 4.86 (2H, d, J=5.6Hz), 7.46 (2H, d, J=8.0Hz), 7.54 (1H, s), 7.90 (2H, d, J=8.0Hz), 8.35 (1H, s), 8.67 (1H, brs)

Example 18 4-(3-Hydroxymethylbenzyl)amino-6,7,8-trimethoxyquinazoline ##STR79##

molecular formula; C₁₉ H₂₁ N₃ O₄

yield (%); 86

m.p. (°C.); amorphous

Mass; 356 (M+H)⁺

NMR δ (CDCl₃); 3.93 (3H, s), 4.03 (3H, s), 4.12 (3H, s), 4.70 (2H, s), 4.86 (2H, d, J=5.2Hz), 5.82 (1H, brs), 6.72 (1H, s), 7.3˜7.4 (4H, m), 8.63 (1H, s)

Example 19 4-(3,4-Dichlorobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR80##

molecular formula; C₁₈ H₁₇ N₃ O₃ Cl₂

yield (%); 85

m.p. (°C.); 205˜206

Mass; 394 (M+H)⁺

NMR δ (CDCl₃); 3.97 (3H, s), 4.04 (3H, s), 4.12 (3H, s), 4.84 (2H, d, J=5.6Hz), 5.88 (1H, brs), 6.74 (1H, s), 7.24 (1H, d, J=8.4Hz), 7.40 (1H, d, J=8.4Hz), 7.47 (1H, s), 8.63 (1H, s)

Example 20 4-(3-Chloro-4-methoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR81##

molecular formula; C₁₉ H₂₀ N₃ O₄ Cl

yield (%); 83

m.p. (°C.); 164˜165

Mass; 390 (M+H)⁺

NMR δ (CDCl₃); 3.90 (3H, s), 3.97 (3H, s), 4.04 (3H, s), 4.13 (3H, s), 4.80 (2H, d, J=5.2Hz), 5.90 (1H, brs), 6.75 (1H, s), 6.91 (1H, d, J=8.8Hz), 7.30 (1H, dd, J=8.8 Hz, 2.0Hz), 7.43 (1H, d, J=2.0Hz), 8.65 (1H, s)

Example 21 4-(3,4-Difluorobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR82##

molecular formula; C₁₈ H₁₇ N₃ O₃ F₂

yield (%); 96

m.p. (°C.); 175˜177

Mass; 362 (M+H)⁺

NMR δ (CDCl₃); 3.97 (3H, s), 4.04 (3H, s), 4.13 (3H, s), 4.85 (2H, d, J=5.2Hz), 5.73 (1H, brs), 6.69 (1H, s), 7.1˜7.3 (3H, m), 8.64 (1H, s)

Example 22 4-(3-Fluoro-4-methoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR83##

molecular formula; C₁₉ H₂₀ N₃ O₄ F

yield (%); 82

m.p. (°C.); 171˜172

Mass; 374 (M+H)⁺

NMR δ (CDCl₃); 3.89 (3H, s), 3.98 (3H, s), 4.04 (3H, s), 4.12 (3H, s), 4.81 (2H, d, J=5.6Hz), 6.27 (1H, brs), 6.86 (1H, s), 6.94 (1H, m), 7.14˜7.19 (2H, m), 8.64 (1H, s)

Example 23 4-(3,4-Dimethoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR84##

molecular formula; C₂₀ H₂₃ N₃ O₅

yield (%); 32

m.p. (°C.); 171˜172

Mass; 386 (M+H)⁺

NMR δ (CDCl₃); 3.87 (3H, s), 3.89 (3H, s), 3.94 (3H, s), 4.03 (3H, s), 4.13 (3H, s), 4.79 (2H, d, J=5.2Hz), 5.67 (1H, brs), 6.69 (1H, s), 6.86 (1H, d, J=8.8Hz), 6.96 (1H, s), 6.98 (1H, d, J=8.8Hz), 8.67 (1H, s)

Example 24 4-(4-Hydroxy-3-methoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR85##

molecular formula; C₁₉ H₂₁ N₃ O₅

yield (%); 16

m.p. (°C.); 201˜202 (dec.)

Mass; 372 (M+H)⁺

NMR δ (CDCl₃); 3.88 (3H, s), 3.96 (3H, s), 4.03 (3H, s), 4.12 (3H, s), 4.78 (2H, d, J=5.2Hz), 6.00 (1H, brs), 6.77 (1H, s), 6.91 (1H, s), 6.92 (1H, s), 6.97 (1H, s), 8.65 (1H, s)

Example 25 4-(3,4-Ethylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR86##

molecular formula; C₂₀ H₂₁ N₃ O₅

yield (%); 92

m.p. (°C.); 217˜219

Mass; 384 (M+H)⁺

NMR δ (CDCl₃); 3.95 (3H, s), 4.03 (3H, s), 4.13 (3H, s), 4.26 (4H, s), 4.75 (2H, d, J=5.2Hz), 5.54 (1H, brs), 6.64 (1H, s), 6.87 (1H, d, J=8.0Hz), 6.90 (1H, d, J=8.0Hz), 6.94 (1H, s), 8.66 (1H, s)

Example 26 4-(3-Allyl-4-methoxymethoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR87##

molecular formula; C₂₃ H₂₇ N₃ O₅

yield (%); 49

m.p. (°C.); 120˜121

Mass; 426 (M+H)⁺

NMR δ (CDCl₃); 3.41 (2H, d, J=6.8Hz), 3.48 (3H, s), 3.94 (3H, s), 4.03 (3H, s), 4.12 (3H, s), 4.77 (2H, d, J=5.2Hz), 5.06 (2H, m), 5.21 (2H, s), 5.78 (1H, brs), 5.98 (1H, m), 6.71 (1H, s), 7.07 (1H, d, J=8.4Hz), 7.23 (1H, s), 7.24 d, J=8.4Hz), 8.65 (1H, s)

Example 27 4-(Benzimidazol-5-ylmethyl)amino-6,7,8-trimethoxyquinazoline ##STR88##

molecular formula; C₁₉ H₁₉ N₅ O₃

yield (%); 52

m.p. (°C.); 235˜240 (dec.)

Mass; 366 (M+H)⁺

NMR δ (DMSO-d₆); 3.93 (3H, s), 3.95 (3H, s), 3.98 (3H, s), 4.97 (2H, d, J=6.0Hz), 7.30 (1H, dd, J=8.4Hz, 1.6Hz), 7.57 (1H, d, J=8.4Hz), 7.63 (1H, d, J=1.6Hz), 7.83 (1H, s), 8.31 (1H, s), 8.36 (1H, brs), 8.52 (1H, s), 9.76 (1H, brs)

Example 28 4-(4-Benzyloxy-3-nitrobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR89##

molecular formula; C₂₅ H₂₄ N₄ O₆

yield (%); 81

m.p. (°C.); 181˜182

Mass; 477 (M+H)⁺

NMR δ (CDCl₃); 3.98 (3H, s), 4.03 (3H, s), 4.10 (3H, s), 4.85 (2H, d, J=5.2Hz), 5.21 (2H, s), 6.54 (1H, brs), 6.93 (1H, s), 7.06 (1H, d, J=8.4Hz), 7.30˜7.45 (5H, m), 7.60 (1H, dd, J=8.4Hz, 2.4Hz), 7.87 (1H, d, J=2.4Hz), 8.61 (1H, s)

Example 29 4-(4-Chloro-3-nitrobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR90##

molecular formula; C₁₈ H₁₇ N₄ O₅ Cl

yield (%); 88

m.p. (°C.); 218˜219 (dec.)

Mass; 405 (M+H)⁺

NMR δ (CDCl₃); 3.98 (3H, s), 4.04 (3H, s), 4.13 (3H, s), 4.93 (2H, d, J=6.0Hz), 5.98 (1H, brs), 6.75 (1H, s), 7.50 (1H, d, J=8.4Hz), 7.58 (1H, dd, J=8.4Hz, 2.0Hz), 7.87 (1H, d, J=2.0Hz), 8.61 (1H, s)

Example 30 4-(2-Propoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR91##

molecular formula; C₂₁ H₂₅ N₃ O₄

yield (%); 80

m.p. (°C.); 139˜140

Mass; 384 (M+H)⁺

NMR δ (CDCl₃); 1.07 (3H, t, J=7.4Hz), 1.85 (2H, m), 3.95 (3H, s), 4.02 (3H, s), 4.02 (2H, t, J=6.4Hz), 4.10 (3H, s), 4.89 (2H, d, J=5.6Hz), 6.72 (1H, s), 6.9 (2H, m), 7.28 (1H, m), 7.38 (1H, d, J=7.2Hz), 8.64 (1H, s)

Example 31 4-(2,4,6-Trimethoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR92##

molecular formula; C₂₁ H₂₅ N₃ O₆

yield (%); 64

m.p. (°C.); 213˜215

Mass; 416 (M+H)⁺

NMR δ (CDCl₃); 3.85 (9H, s), 3.92 (3H, s), 4.01 (3H, s), 4.11 (3H, s), 4.79 (2H, d, J=4.4Hz), 5.65 (1H, brs), 6.20 (2H, s), 6.60 (1H, s), 8.68 (1H, s)

Example 32 4-(3,4,5-Trimethoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR93##

molecular formula; C₂₁ H₂₅ N₃ O₆

yield (%); 60

m.p. (°C.); 153˜154

NMR δ (CDCl₃); 3.85 (9H, s), 3.97 (3H, s), 4.03 (3H, s), 4.13 (3H, s), 4.80 (2H, d, J=5.6Hz), 6.66 (2H, s), 6.80 (1H, s), 8.66 (1H, s)

Example 33 4-(2-Chloro-4,5-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR94##

molecular formula; C₁₉ H₁₈ N₃ O₅ Cl

yield (%); 76

m.p. (°C.); 220˜221

Mass; 404 (M+H)⁺

NMR δ (CDCl₃); 3.97 (3H, s), 4.02 (3H, s), 4.11 (3H, s), 4.86 (2H, d, J=6.0Hz), 5.95 (2H, s), 6.70 (1H, brt, J=6.0Hz), 6.86 (1H, s), 6.95 (1H, s), 6.98 (1H, s), 8.61 (1H, s)

Example 34 4-(4,5-Methylenedioxy-2-nitrobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR95##

molecular formula; C₁₉ H₁₈ N₄ O₇

yield (%); 15

m.p. (°C.); 182˜183

Mass; 415 (M+H)⁺

NMR δ (CDCl₃); 3.99 (3H, s), 4.02 (3H, s), 4.10 (3H, s), 5.08 (2H, d, J=6.4Hz), 6.09 (2H, s), 6.82 (2H, s & brs), 7.27 (1H, s), 7.57 (1H, s), 8.61 (1H, s)

Example 35 4-[2-(4-Nitrophenyl)ethyl]amino-6,7,8-trimethoxyquinazoline ##STR96##

molecular formula; C₁₉ H₂₀ N₄ O₅

yield (%); 58

m.p. (°C.); 152˜153

Mass; 385 (M+H)⁺

NMR δ (CDCl₃); 3.18 (2H, t, J=7.2Hz), 3.92 (3H, s), 3.96 (3H, m), 4.04 (3H, s), 4.13 (3H, s), 5.57 brs), 6.58 (1H, s), 7.41 (2H, d, J=8.8Hz), 8.17 (2H, d, J=8.8Hz), 8.66 (1H, s)

Example 36 4-[2-(3,4-Methylenedioxyphenyl)ethyl]amino-6,7,8-trimethoxyquinazoline ##STR97##

molecular formula; C₂₀ H₂₁ N₃ O₅

yield (%); 68

m.p. (°C.); 193˜194

Mass; 384 (M+H)⁺

NMR δ (CDCl₃); 2.96 (2H, t, J=6.8Hz), 3.87 (2H, m), 3.93 (3H, s), 4.03 (3H, s), 4.12 (3H, s), 5.43 (1H, brs), 5.95 (2H, s), 6.52 (1H, s), 6.71 (1H, d, J=8.0Hz), 6.77 (1H, s), 6.78 (1H, d, J=8.0Hz), 8.65 (1H, s)

Example 37 4-[2-(Imidazol-4-yl)ethyl]amino-6,7,8-trimethoxyquinazoline ##STR98##

molecular formula; C₁₆ H₁₉ N₅ O₃

yield (%); 77

m.p. (°C.); 164˜166 (dec.)

Mass; 330 (M+H)⁺

NMR δ (DMSO-d₆); 3.00 (2H, t, J=7.2Hz), 3.81 (2H, m), 3.87 (3H, s), 3.92 (3H, s), 3.97 (3H, s), 7.25 (1H, s), 7.56 (1H, s), 8.39 (1H, s), 8.45 (1H, s), 8.50 (1H, brs)

Example 38 4-(α-Methyl-3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazolin ##STR99##

molecular formula; C₂₀ H₂₁ N₃ O₅

yield (R); 67

m.p. (°C.); 200˜201

Mass; 384 (M+H)⁺

NMR δ (CDCl); 1.67 (2H, d, J=6.8Hz), 3.99 (3H, s), 4.04 (3H, s), 4.13 (3H, s), 5.47 (1H, brs), 5.57 (1H, t, J=6.8Hz), 5.97 (2H, s), 6.65 (1H, s), 6.81 (1H, d, J=7.6Hz), 6.94 (1H, d, J=7.6Hz), 6.95 (1H, s), 8.63 (1H, s)

Example 39 4-[1-Methyl-1-(3,4-methylenedioxyphenyl)ethyl]amino-6,7,8-trimethoxyquinazoline ##STR100##

molecular formula; C₂₁ H₂₃ N₃ O₅

yield (%); 4

m.p. (°C.); 191˜192

Mass; 398 (M+H)⁺

NMR δ (CDCl₃); 1.90 (6H, s), 4.03 (3H, s), 4.03 (3H, s), 4.09 (3H, s), 5.93 (2H, s), 6.74 (1H, d, J=7.6Hz), 6.82 (1H, s), 6.92 (2H, m), 8.46 (1H, s)

Example 40 4-[N-Ethyl-(3,4-methylenedioxybenzyl)amino]-6,7,8-trimethoxyquinazoline ##STR101##

molecular formula; C₂₁ H₂₃ N₃ O₅

yield (%); 73

m.p. (°C.); 100˜101

Mass; 398 (M+H)⁺

NMR δ (CDCl₃); 1.37 (3H, t, J=7.0Hz), 3.56 (3H, s), 3.67 (2H, q, J=7.0Hz), 4.03 (3H, s), 4.11 (3H, s), 4.79 (2H, s), 5.98 (2H, s), 6.85 (1H, d, J=7.2Hz), 6.93 (1H, s), 6.93 (1H, d, J=7.2Hz), 6.97 (1H, s), 8.69 (1H, s)

Example 41 4-[N-(Ethoxycarbonylmethyl)-(3,4-methylenedioxybenzyl)amino]-6,7,8-trimethoxyquinazoline ##STR102##

molecular formula; C₂₃ H₂₅ N₃ O₇

yield (%); 41

m.p. (°C.); oily substance

Mass; 456 (M+H)⁺

NMR δ (CDCl₃); 1.29 (3H, t, J=7.2Hz), 3.44 (8H, s), 4.02 (3H, s), 4.10 (3H, s), 4.20 (2H, s), 4.25 (2H, q, J=7.2Hz), 4.98 (2H, s), 6.00 (2H, s), 6.88 (1H, d, J=8.0Hz), 6.97(1H, s), 7.01 (1H, d, J=8.0Hz), 8.64 (1H, s)

Example 42 4-[N-(2-Methoxyethyl)-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR103##

molecular formula; C₂₂ H₂₅ N₃ O₆

yield (%); 21

m.p. (°C.); 87˜88

Mass; 428 (M+H)⁺

NMR δ (CDCl₃); 3.36 (3H, s), 3.58 (3H, s), 3.80˜3.85 (4H, m), 4.02 (3H, s), 4.10 (3H, s), 4.92 (2H, s), 5.97 (2H, s), 6.83 (1H, d, J=7.6Hz), 6.92 (1H, d, J=7.6Hz), 6.94 (1H, s), 7.19 (1H, s), 8.67 (1H, s)

Example 43 4-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-6,7,8-trimethoxyquinazoline ##STR104##

molecular formula; C₂₂ H₂₅ N₃ O₅

yield (%); 79

m.p. (°C.); 157˜158

Mass; 412 (M+H)⁺

NMR δ (CDCl₃); 3.11 (2H, t, J=5.8Hz), 3.87 (3H, s), 3.89 (3H, s), 3.96 (2H, t, J=5.8Hz), 3.99 (3H, s), 4.07 (3H, s), 4.14 (3H, s), 4.80 (2H, s), 6.67 (1H, s), 6.71 (1H, s), 7.03 (1H, s), 8.74 (1H, s)

Example 44 4-[4-(1-Hydroxyethyl)benzyl]amino-6-methoxyquinazoline ##STR105##

molecular formula; C₁₈ H₁₉ N₃ O₂

yield (%); 46

m.p. (°C.); amorphous

Mass; 310 (M+H)⁺

NMR δ (CDCl₃); 1.47 (2H, d, J=6.4Hz), 3.91 (3H, s), 4.87 (2H, d, J=5.2Hz), 4.84˜4.94 (1H, m), 7.34˜7.42 (6H, m), 7.59 (1H, brs), 7.79 (1H, d, J=8.8Hz), 8.52 (1H, s)

Example 45 4-(Benzimidazol-5-ylmethyl)amino-6-methoxyquinazoline ##STR106##

molecular formula; C₁₇ H₁₅ N₅ O

yield (%); 18

m.p. (°C.); 254˜255

Mass; 306 (M+1)⁺

NMR δ (DMSO-d₆); 3.88 (3H, s), 4.91 (2H, d, J=6.0Hz), 7.24 (1H, d, J=8.4Hz), 7.40 (1H, dd, J=9.2Hz, 2.8Hz), 7.54 (1H, d, J=8.4Hz), 7.56 (1H, s), 7.63 (1H, d, J=9.2Hz), 7.73 (1H, d, J=2.8Hz), 8.16 (1H, s), 8.37 (1H, s), 8.67 (1H, t, J=6.0Hz), 12.33 (1H, brs)

Example 46 4-(3,4-Methylenedioxybenzyl)amino-6-methoxyquinazoline ##STR107##

molecular formula; C₁₇ H₁₅ N₃ O₃

yield (%); 86

m.p. (°C.); 207˜208

Mass; 310 (M+H)⁺

NMR δ (CDCl₃); 3.89 (3H, s), 4.78 (2H, d, J=5.2Hz), 5.70 (1H, brs), 5.97 (2H, s), 6.80 (1H, d, J=7.6Hz), 6.9 (3H, m), 7.40 (1H, d, J=9.2Hz), 7.80 (1H, d, J=9.2Hz), 8.63 (1H, s)

Example 47 4-[2-(3,4-Methylenedioxyphenyl)pyrrolidino]-6-methoxyquinazoline ##STR108##

molecular formula; C₂₀ H₁₉ N₃ O₃

yield (%); 85

m.p. (°C.); oily substance

Mass; 350 (M+1)⁺

NMR δ (CDCl₃); 1.95˜2.10 (3H, m), 2.37 (1H, m), 3.58 (3H, s), 4.05˜4.20 (2H, m), 5.58 (1H, m), 5.93 (1H, s), 5.94 (1H, s), 6.78 (1H, d, J=8.4Hz), 6.84 (1H, s), 6.85 (1H, d, J=8.4Hz), 7.30 (1H, d, J=10.0Hz), 7.35 (1H, s), 7.74 (1H, d, J=10.0Hz), 8.53 (1H, s)

Example 48 4-(4-Methoxy-3-nitrobenzyl)amino-6-methoxyquinazoline ##STR109##

molecular formula; C₁₇ H₁₆ N₄ O₄

yield (%); 22

m.p. (°C.); 205˜206 (dec.)

Mass; 341 (M+1)⁺

NMR δ (CDCl₃); 3.93 (3H, s), 3.94 (3H, s), 4.91 (2H, d, J=6.0Hz), 7.07 (1H, dd, J=8.4Hz, 1.2Hz), 7.21 (1H, d, J=1.2Hz), 7.39 (1H, dd, J=9.2Hz, 2.4Hz), 7.53 (1H, d, J=2.4Hz), 7.75 (1H, d, J=9.2Hz), 7.82 (1H, d, J=8.4Hz), 8.03 (1H, brs), 8.51 (1H, s)

Example 49 4-(3,4-Methylenedioxybenzyl)amino-6-methylthioquinazoline ##STR110##

4.12 g (0.0196 mol) of 4-chloro-6-methylthioquinazoline, 3.70 g (0.0245 mol) of piperonylamine and 3.50 g (0.0330 mol) of sodium carbonate were mixed with 100 ml of isopropyl alcohol. The obtained mixture was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from chloroform/n-hexane to give 5.32 g of the title compound as a pale-yellow crystal.

molecular formula; C₁₇ H₁₅ O₂ N₃ S

yield (%); 83

m.p. (°C.); 174˜175

Mass; 326 (M+H)⁺

NMR δ (CDCl₃); 2.59 (3H, s), 4.79 (2H, d, J=5.6Hz), 5.93 (2H, s), 6.77 (1H, d, J=8.0Hz), 6.89 (1H, d, J=8.0Hz), 6.94 (1H, s), 7.62 (1H, dd, J=8.8Hz, 2.0Hz), 7.75 (1H, d, J=8.8Hz), 7.97 (1H, d, J=2.0Hz), 8.10 (1H, brs), 8.56 (1H, s)

Examples 50 to 54

The following compounds were prepared in a similar manner to that of Example 49.

Example 50 4-(3,4-Dichlorobenzyl)amino-6-methylthioquinazoline ##STR111##

molecular formula; C₁₆ H₁₃ N₃ SCl₂

yield (%); 85

m.p. (°C.); 184˜185

Mass; 350 (M+H)⁺

NMR δ (CDCl₃); 2.61 (3H, s), 4.83 (2H, d, J=5.6Hz), 7.28 (1H, dd, J=8.4Hz, 2.0Hz), 7.40 (1H, d, J=8.4Hz), 7.51 (1H, d, J=2.0Hz), 7.64 (1H, dd, J=8.8Hz, 2.0Hz), 7.76 (1H, d, J=8.8Hz), 7.97 (1H, d, J=2.0Hz), 8.19 (1H, brs), 8.55 (1H, s)

Example 51 4-(3-Fluoro-4-methoxybenzyl)amino-6-methylthioquinazoline ##STR112##

molecular formula; C₁₇ H₁₆ N₃ OSF

yield (%); 89

m.p. (°C.); 168˜169

Mass; 330 (M+H)⁺

NMR δ (CDCl₃); 2.58 (3H, s), 3.90 (3H, s), 4.82 (2H, d, J=5.6Hz), 6.29 (1H, brs), 6.95 (1H, m), 7.13˜7.18 (2H, m), 7.54 (1H, s), 7.63 (1H, d, J=8.8Hz), 7.79 (1H, d, J=8.8Hz), 8.64 (1H, s)

Example 52 4-(Benzimidazol-5-ylmethyl)amino-6-methylthioquinazoline ##STR113##

molecular formula; C₁₇ H₁₅ N₅ S

yield (%); 48

m.p. (°C.); 271˜275 (dec.)

Mass; 322 (M+H)⁺

NMR δ (DMSO-d₆); 2.67 (3H, s), 5.06 (2H, d, J=5.6Hz), 7.47 (1H, d, J=8.4Hz), 7.68 (1H, d, J=8.8Hz), 7.77 (2H, m), 7.87 (1H, d, J=8.8Hz), 8.40 (1H, s), 8.77 (1H, s), 8.84 (1H, s), 10.68 (1H, brs)

Example 53 4-[N-(2-Methoxyethyl)-(3,4-methylenedioxybenzyl)amino]-6-methylthioquinazoline ##STR114##

molecular formula; C₂₀ H₂₁ N₃ O₃ S

yield (%); 27

m.p. (°C.); 92˜93

Mass; 384 (M+H)⁺

NMR δ (CDCl₃); 2.16 (3H, s), 3.35 (3H, s), 3.82 (2H, t, J=5.0Hz), 3.89 (2H, t, J=5.0Hz), 5.01 (2H, s), 5.98 (2H, s), 6.84 (1H, d, J=8.4Hz), 6.89 (1H, d, J=8.4Hz), 6.90 (1H, s), 7.56 (1H, dd, J=8.8Hz, 2.0Hz), 7.66 (1H, d, J=2.0Hz), 7.82 (1H, d, J=8.8Hz)

Example 54 4-[N-(2-Hydroxyethyl)-(3,4-methylenedioxybenzyl)amino]-β-methylthioquinazoline ##STR115##

molecular formula; C₁₉ H₁₉ N₃ O₃ S

yield (%); 21

m.p. (°C.); 146˜147 (dec.)

Mass: 870 (M+H)⁺

NMR δ (CDCl₃); 2.00 (3H, s), 3.93 (2H, t, J=4.2Hz), 4.01 (2H, t, J=4.2Hz), 5.00 (2H, s), 6.01 (2H, s), 6.89 (3H, m), 7.57 (2H, m), 7.82 (1H, d, J=9.2Hz), 8.55 (1H, s)

Example 55 4-(4-Chloro-3-nitrobenzyl)amino-6-chloroquinazoline ##STR116##

3.00 g (0.015 mol) of 4,6-dichloroquinazoline and 3.80 g (0.0170 mol) of 4-chloro-3-nitrobenzylamine hydrochloride were dissolved in a mixture comprising 100 ml of isopropyl alcohol and 15 ml of triethylamine. The obtained solution was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate) and recrystallized from chloroform/n-hexane to give 4.85 g of the title compound as a pale-yellow crystal.

molecular formula; C₁₅ H₁₀ N₄ O₂ Cl₂

yield (%); 92

m.p. (°C.); 199˜200

Mass; 349 (M+H)⁺

NMR δ (CDCl₃); 4.85 (2H, d, J=6.0Hz), 7.49 (1H, d, J=8.4Hz), 7.61 (1H, dd J=8.4Hz, 2.0Hz), 7.66 (1H, dd, J=8.8Hz, 2.0Hz), 7.76 (1H, d, J=8.8Hz), 7.96 (1H, d, J=2.0Hz), 8.20 (1H, d, J=2.0Hz), 8.23 (1H, brt, J=6.0Hz), 8.58 (1H, s)

Example 56 4-(α-Ethoxycarbonyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR117##

30 ml of 2-propanol, 1.07 g of triethylamine and 1.01 g of α-ethoxycarbonyl-3,4-methylenedioxybenzylamine were added to 704 mg of 4,6-dichloroquinazoline. The obtained mixture was refluxed for 4 hours, followed by the addition of water. The obtained mixture was extracted with chloroform thrice. The chloroform layers were combined, dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The residue was recrystallized (from ethanol/ethyl acetate/hexane) to give 1.167 g of the title compound.

molecular formula; C₁₉ H₁₆ N₃ O₄ Cl

yield (%); 88

m.p. (°C.); 169˜170

Mass m/e; 386 (M+1)

NMR δ (CDCl₃); 1.28 (3H, t, J=7.2Hz), 4.27 (2H, m), 5.85 (1H, d, J=6.4Hz), 5.98 (2H, s), 6.70 (1H, brs), 6.81 (1H, d, J=8.8Hz), 6.99 (2H, m), 7.10 (1H, dd, J=8.8Hz, 2.4Hz), 7.83 (1H, d, J=2.4Hz), 8.85 (1H, d, J=8.8Hz), 8.63 (1H, s)

Examples 57 to 64

The following compounds were prepared in a similar manner to that of Example 56 or 57.

Example 57 4-(3,4-Methylenedioxybenzyl)amino-6-chloroquinazoline ##STR118##

molecular formula; C₁₆ H₁₂ N₃ O₂ Cl

yield (%); 76

m.p. (°C.); 199˜200

Mass; 314 (M+H)⁺

NMR δ (CDCl₃); 4.76 (2H, d, J=5.6Hz), 5.82 (1H, brs), 5.98 (2H, s), 6.81 (1H, d, J=8.0Hz), 6.87 (1H, d, J=8.0Hz), 6.89 (1H, s), 7.67 (1H, s), 7.69 (1H, d, J=8.0Hz), 7.81 (1H, d, J=8.0Hz), 8.70 (1H, s)

Example 58 4-(3,4-Dichlorobenzyl)amino-6-chloroquinazoline ##STR119##

molecular formula; C₁₅ H₁₀ N₃ Cl₃

yield (%); 72

m.p. (°C.); 215˜216

Mass; 338 (M+H)⁺

NMR δ (CDCl₃); 4.85 (2H, d, J=5.6Hz), 5.94 (1H, brs), 7.24 (1H, d, J=8.4Hz), 7.43 (1H, d, J=8.4Hz), 7.70 (1H, d, J=9.2Hz), 7.72 (1H, s), 7.83 (1H, d, J=9.2Hz), 8.68 (1H, s)

Example 59 4-(3,4-Dimethoxybenzyl)amino-6-chloroquinazoline ##STR120##

molecular formula; C₁₇ H₁₆ N₃ O₂ Cl

yield (%); 73

m.p. (°C.); 174˜175

Mass; 330 (M+H)⁺

NMR δ (CDCl₃); 3.87 (6H, s), 4.78 (2H, d, J=5.2Hz), 6.85 (1H, d, J=8.0Hz), 6.96 (1H, d, J=8.0Hz), 6.98 (1H, s), 7.34 (1H, brs), 7.65 (1H, dd, J=9.2Hz, 2.0Hz), 7.78 (1H, d, J=9.2Hz), 8.08 (1H, d, J=2.0Hz), 8.65 (1H, s)

Example 60 4-(Benzimidazol-5-ylmethyl)amino-6-chloroquinazoline ##STR121##

molecular formula; C₁₆ H₁₂ N₅ Cl

yield (%); 76

m.p. (°C.); 243˜244 (dec.)

Mass; 310 (M+H)⁺

NMR δ (DMSO-d₆); 4.89 (2H, d, J=5.6Hz), 7.27 (1H, d, J=8.4Hz) 7.55 (1H, d, J=8.4Hz), 7.59 (1H, s), 7.72 (1H, d, J=8.8Hz), 7.80 (1H, dd, J=8.8Hz, 2.4Hz), 8.25 (1H, s), 8.50 (1H, s), 8.53 (1H, d, J=2.4Hz), 9.07 (1H, brt, J=5.6Hz)

Example 61 4-(2-Methoxy-2,3-dihydrobenzofuran-5-yl)methylamino-6-chloroquinazoline ##STR122##

molecular formula; C₁₈ H₁₆ N₃ O₂ Cl (341.798)

yield (%); 53

m.p. (°C.); 178˜179

Mass; 342 (MH)⁺

NMR δ (DMSO-d₆); 2.88 (1H, dd, J=2.0Hz, 17.0Hz), 3.28˜3.34 (1H, m), 4.68 (1H, d, J=5.7Hz), 5.68 (1H, dd, J=2.0Hz, 6.6Hz), 6.79 (1H, d, J=8.2Hz), 7.14 (1H, d, J=8.2Hz), 7.24 (1H, s), 7.70 (1H, d, J=9.0Hz), 7.79 (1H, dd, J=2.2Hz, 9.0Hz), 8.46 (1H, d, J=2.2Hz), 8.48 (1H, s), 8.82 (1H, t, J=5.7Hz)

Example 62 4-(2-Methylbenzimidazol-5-ylmethyl)amino-6-chloroquinazoline ##STR123##

molecular formula; C₁₇ H₁₄ N₅ Cl

yield (%); 17

m.p. (°C.); 273˜274 (dec.)

Mass; 324 (M+H)⁺

NMR δ (DMSO-d₆); 2.71 (3H, s), 4.94 (2H, d, J=5.6Hz), 7.48 (1H, d, J=8.4Hz), 7.63 (1H, d, J=8.4Hz), 7.70 (1H, s), 7.77 (1H, d, J=8.8Hz), 7.86 (1H, dd, J=8.8Hz, 2.0Hz), 8.58 (1H, s), 8.65 (1H, d, J=2.0Hz), 9.65 (1H, brs)

Example 63 4-[1-Methyl-1-(3,4-methylenedioxyphenyl)ethyl]amino-6-chloroquinazoline ##STR124##

molecular formula; C₁₈ H₁₆ N₃ O₂ Cl

yield (%); 32

m.p. (°C.); 175˜176

Mass; 342 (M+H)⁺

NMR δ (CDCl₃); 1.92 (6H, s), 5.95 (2H, s), 6.14 (1H, brs), 6.76 (1H, d, J=7.6Hz), 6.92 (1H, d, J=7.6Hz), 6.93 (1H, s), 7.67 (1H, dd, J=8.8Hz), 7.77 (1H, d, J=2.0Hz), 7.86 (1H, d, J=8.8Hz), 8.50 (1H, s)

Example 64 4-(3,4-Methylenedioxybenzyl)amino-6-ethoxyquinazoline ##STR125##

molecular formula; C₁₈ H₁₇ N₃ O₃

yield (%); 44

m.p. (°C.); 190˜191

Mass; 324 (M+H)⁺

NMR δ (CDCl₃); 1.46 (3H, t, J=6.8Hz), 4.10 (2H, q, J=6.8Hz), 4.77 (2H, d, J=5.2Hz), 5.68 (1H, brs), 5.97 (2H, s), 6.80 (1H, d, J=8.0Hz), 6.87˜6.92 (3H, m), 7.39 (1H, dd, J=9.2Hz, 2.8Hz), 7.79 (1H, d, J=9.2Hz), 8.62 (1H, s)

Example 65 4-(3,4-Methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR126##

15 ml of isopropyl alcohol, 75 mg of triethylamine and 125 mg of piperonylamine were added to 140 mg of 4-chloro-6-cyanoquinazoline. The obtained mixture was heated under reflux for 5 hours and filtered to recover a precipitate. This precipitate was introduced to a silica gel column, followed by eluting with ethyl acetate to give 200 mg of the title compound.

molecular formula; C₁₇ H₁₂ N₄ O₂

yield (%); 89

m.p. (°C.); 243˜244

Mass; 305 (M+1)⁺

NMR δ (DMSO-d₆); 4.67 (2H, d, J=5.6Hz), 5.96 (2H, s), 6.84 (2H, s), 6.95 (1H, s), 7.77 (1H, d, J=8.4Hz), 8.56 (1H, s), 8.89 (1H, s), 9.04 (1H, br)

Examples 66 to 87

The following compounds were prepared in a similar manner to that of Example 65.

Example 66 4-[3-(1-Imidazolyl)propyl]amino-6-cyanoquinazoline ##STR127##

molecular formula; C₁₅ H₁₄ N₆

yield (%); 22

m.p. (°C.); 196˜197

Mass m/e; 279 (M+1)

NMR δ (CDCl₃); 2.27 (2H, quintet, J=6.4Hz), 3.66 (2H, q, J=6.4Hz), 4.17 (2H, t, J=6.4Hz), 7.07 (1H, s), 7.11 (1H, s), 7.82 (1H, s), 7.82 (1H, s), 8.09 (1H, s), 8.37 (1H, brs), 8.66 (1H, s), 8.84 (1H, s)

Example 67 4-(Benzimidazol-5-yl)methylamino-6-cyanoquinazoline ##STR128##

molecular formula; C₁₇ H₁₂ N₆

yield (%); 68

m.p. (°C.); 274˜277

Mass; 301 (M+1)⁺

NMR δ (DMSO-d₆); 4.88 (2H, d, J=5.6Hz), 7.21˜7.24 (1H, m), 7.35˜7.76 (2H, m), 7.78 (1H, d, J=8.8Hz), 7.06 (1H, dd, J=8.8Hz, 1.6Hz), 8.15 (1H, s), 8.57 (1H, s), 8.92 (1H, s), 9.14 (1H, m), 12.32 (1H, m)

Example 68 4-(3,4-Methylenedioxybenzyl)amino-6-ethoxycarbonylquinazoline ##STR129##

molecular formula; C₁₉ H₁₇ N₃ O₄

yield (%); 48

m.p. (°C.); 156˜157

Mass; 352 (M+H)⁺

NMR δ (CDCl₃); 1.43 (3H, t, J=7.2Hz), 4.44 (2H, q, J=7.2Hz), 4.79 (2H, d, J=5.2Hz), 5.98 (2H, s), 6.14 (1H, brs), 6.82 (1H, d, J=8.0Hz), 6.89 (1H, d, J=8.0Hz), 6.90 (1H, s), 7.87 (1H, d, J=8.8Hz), 8.33 (1H, d, J=8.8Hz), 8.46 (1H, s), 8.74 (1H, s)

Example 69 4-(3,4-Methylenedioxybenzyl)amino-6-methylquinazoline ##STR130##

molecular formula; C₁₇ H₁₅ N₃ O₂

yield (%); 68

m.p. (°C.); 208˜204

Mass; 294 (M+H)⁺

NMR δ (CDCl₃); 2.49 (3H, s), 4.76 (2H, d, J=5.6Hz), 5.79 (1H, brs), 5.96 (2H, s), 6.81 (1H, d, J=8.0Hz), 6.88 (1H, d, J=8.0Hz), 6.91 (1H, s), 7.44 (1H, s), 7.57 (1H, d, J=8.4Hz), 7.76 (1H, d, J=8.4Hz), 8.66 (1H, s)

Example 70 4-(3,4-Methylenedioxybenzyl)amino-6,7-dimethoxyquinazoline ##STR131##

molecular formula; C₁₈ H₁₇ N₃ O₄

yield (%); 77

m.p. (°C.); 221˜222

Mass; 340 (M+H)⁺

NMR δ (DMSO-d₆); 3.88 (3H, s), 3.89 (3H, s), 4.68 (2H, d, J=6.0Hz), 5.97 (2H, s), 6.85 (2H, s), 6.94 (1H, s), 7.09 (1H, s), 7.64 (1H, s), 8.33 (1H, s), 8.37 (1H, t, J=6.0Hz)

Example 71 4-(3,4-Methylenedioxybenzyl)amino-6,8-dimethoxyquinazoline ##STR132##

molecular formula; C₁₈ H₁₇ N₃ O₄

yield (%); 88

m.p. (°C.); 217˜218

Mass; 340 (M+H)⁺

NMR δ (CDCl₃); 3.89 (3H, s), 4.01 (3H, s), 4.77 (2H, d, J=5.2Hz), 5.63 (1H, brs), 5.97 (2H, s), 6.42 (1H, d, J=2.4Hz), 6.77 (1H, d, J=2.4Hz), 6.80 (1H, d, J=7.6Hz), 6.88 (1H, dd, J=7.6Hz, 1.6Hz), 6.92 (1H, d, J=1.6Hz), 8.65 (1H, s)

Example 72 4-(3,4-Methylenedioxybenzyl)amino-5,6-dimethoxyquinazoline ##STR133##

molecular formula; C₁₈ H₁₇ N₃ O₄

yield (%); 74

m.p. (°C.); 122˜123

Mass; 340 (M+1)⁺

NMR δ (CDCl₃); 3.97 (6H, s), 4.77 (2H, d, J=5.2Hz), 5.97 (2H, s), 6.81 (1H, d, J=8.0Hz), 6.86 (1H, dd, J=8.0Hz, 1.6Hz), 6.88 (1H, d, J=1.6Hz), 7.49 (1H, d, J=8.8Hz), 7.82 (1H, d, J=8.8Hz), 8.51 (1H, s), 8.64 (1H, brs)

Example 73 4-(3,4-Methylenedioxybenzyl)amino-6-acetamido-7-methoxyquinazoline ##STR134##

molecular formula; C₁₉ H₁₈ N₄ O₄

yield (%); 66

m.p. (°C.); 164˜165

Mass; 367 (M+H)⁺

NMR δ (CDCl₃); 2.26 (3H, s), 4.04 (3H, s), 4.76 (2H, d, J=5.6Hz), 5.95 (2H, s), 6.22 (1H, brs), 6.77 (1H, d, J=8.0Hz), 6.85 (1H, d, J=8.0Hz), 6.89 (1H, s), 7.31 (1H, s), 8.02 (1H, brs), 8.59 (1H, s ), 8.81 (1H, s)

Example 74 4-(3,4-Methylenedioxybenzyl)amino-6-methylthio-7-methoxyquinazoline ##STR135##

molecular formula; C₁₈ H₁₇ N₃ O₃ S

yield (%); 39

m.p. (°C.); 200˜205 (dec.)

Mass; 356 (M+H)⁺

NMR δ (CDCl₃); 2.50 (3H, s), 4.01 (3H, s), 4.78 (2H, d, J=5.6Hz), 5.95 (2H, s), 6.13 (1H, brs), 6.79 (1H, d, J=8.0Hz), 6.88 (1H, d, J=8.0Hz), 6.91 (1H, s), 7.15 (1H, s), 7.33 (1H, s), 8.56 (1H, s)

Example 75 4-(3,4-Methylededioxybenzyl)aminoquinazoline ##STR136##

molecular formula; C₁₆ H₁₃ N₃ O₂

yield (%); 69

m.p. (°C.); 197˜198

Mass; 280 (M+H)⁺

NMR δ (CDCl₃); 4.78 (2H, d, J=5.2Hz), 5.85 (1H, brs), 5.96 (2H, s), 6.80 (1H, d, J=8.0Hz), 6.88 (1H, d, J=8.0Hz), 6.91 (1H, s), 7.46 (1H, t, J=8.0Hz), 7.68 (1H, d, J=8.0Hz), 7.75 (1H, t, J=8.0Hz), 7.87 (1H, d, J=8.0Hz), 8.71 (1H, s)

Example 76 4-(3,4-Methylededioxybenzyl)amino-8-methoxyquinazoline ##STR137##

molecular formula; C₁₇ H₁₅ N₃ O₃

yield (%); 76

m.p. (°C.); 195˜196

Mass; 310 (M+H)⁺

NMR δ (CDCl₃); 4.03 (3H, s), 4.78 (2H, d, J=5.6Hz), 5.94 (2H, s), 6.77 (1H, d, J=8.0Hz), 6.89 (1H, d, J=8.0Hz), 6.92 (1H, s), 6.95 (1H, brs), 7.12 (1H, d, J=8.0Hz), 7.89 (1H, t, J=8.0Hz), 7.48 (1H, d, J=8.0Hz), 8.70 (1H, s)

Example 77 4-(3,4-Methylenedioxybenzyl)amino-7-chloroquinazoline ##STR138##

molecular formula; C₂₁ H₂₂ N₃ O₂ Cl

yield (%); 62

m.p. (°C.); 209˜210

Mass; 314 (M+H)⁺

NMR δ (CDCl₃); 4.77 (2H, d, J=5.6Hz), 5.95 (2H, s), 6.78 (1H, d J=8.0Hz), 6.88 (1H, d, J=8.0Hz), 6.92 (1H, s), 7.39 (1H, dd, J=8.8Hz, 2.0Hz), 7.4 (1H, brs), 7.83 (1H, d, J=2.0Hz), 7.96 (1H, d, J=8.8Hz), 8.63 (1H, s)

Example 78 4-(3,4-Methylenedioxybenzyl)aminobenzo[g]quinazoline ##STR139##

molecular formula; C₂₀ H₁₅ N₃ O₂ (329)

yield (%); 45

m.p. (°C.); 265 (dec.)

Mass; 330 (M+1)⁺

NMR δ (DMSO-d₆); 4.92 (2H, d, J=6.0Hz), 5.97 (2H, s), 6.88 (1H, d, J=8.0Hz), 6.94 (1H, dd, J=8.0Hz, 1.6Hz), 7.06 (1H, d, J=1.6Hz), 7.68˜7.81 (2H, m), 8.11 (1H, d, J=8.4Hz), 8.21 (1H, d, J=8.4Hz), 8.33 (1H, s), 8.90 (1H, s), 9.36 (1H, s), 11.09 (1H, br)

Example 79 4-(3,4-Methylenebenzyl)amino-6,7-methylenedioxyquinazoline ##STR140##

molecular formula; C₁₇ H₁₃ N₃ O₄ (323)

yield (%); 55

m.p. (°C.); 229˜231

Mass; 324 (M+1)⁺

NMR δ (DMSO-d₆); 4.62 (2H, d, J=5.6Hz), 5.94 (2H, s), 6.16 (2H, s), 6.79 (1H, d, J=8.0Hz), 6.82 (1H, dd, J=8.0Hz, 2.0Hz), 6.89 (1H, d, J=2.0Hz), 7.06 (1H, s), 7.68 (1H, s), 8.26 (1H, brt, J=5.6Hz), 8.28 (1H, s)

Example 80 4-(3,4,5-Trimethoxybenzyl)amino-6,7-methylenedioxyquinazoline ##STR141##

molecular formula; C₁₉ H₁₉ N₃ O₅ (369)

yield (%); 59

m.p. (°C.); 240˜241

Mass; 370 (M+1)⁺

NMR δ (DMSO-d₆); 3.61 (3H, s), 3.70 (6H, s), 4.65 (2H, d, J=6.0Hz), 6.16 (2H, s), 6.675 (2H, s), 7.06 (1H, s), 7.72 (1H, s), 8.23 (1H, brt, J=6.0Hz), 8.30 (1H, s)

Example 81 2-Methyl-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR142##

molecular formula; C₂₀ H₂₁ N₃ O₅

yield (%); 58

m.p. (°C.); 190˜191

Mass; 384 (M+H)⁺

NMR δ (CDCl₃); 2.67 (3H, s), 3.93 (3H, s), 4.01 (3H, s), 4,11 (3H, s), 4.77 (2H, d, J=5.2Hz), 5.96 (2H, 6.70 (1H, s) 6.79 (1H, d, J=7.6Hz), 6.89 (1H, d, J=7.6Hz), 6.93 (1H, s)

Example 82 2-Isopropyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline ##STR143##

molecular formula; C₂₀ H₂₁ N₃ O₃

yield (%); 84

m.p. (°C.); 157˜158

Mass; 352 (M+1)⁺

NMR δ (CDCl₃); 1.36 (6H, d, J=6.8Hz), 3.15 (1H, septet, J=6.8Hz), 3.88 (3H, s), 4.81 (2H, d, J=5.6Hz), 5.94 (2H, s), 6.78 (1H, d, J=8.0Hz), 6.91 (1H, dd, J=8.0Hz, 2.0Hz), 6.96 (1H, d, J=2.0Hz), 6.99 (1H, brd, J=2.4Hz), 7.32 (1H, dd, J=9.2Hz, 2.4Hz), 7.79 (1H, d, J=9.2Hz)

Example 83 2-(2-Propoxyphenyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR144##

molecular formula; C₂₅ H₂₂ N₃ O₃ Cl

yield (%); 20

m.p. (°C.); 208˜209

Mass; 446 (M+1)⁺

NMR δ (CDCl₃); 0.97 (3H, t, J=7.6Hz), 1.71˜1.81 (2H, m), 4.01 (2H, t, J=6.4Hz), 4.81 (2H, brs), 5.80 (1H, br), 5.96 (2H, s), 6.79˜7.86 (10H, m)

Example 84 2-(2-Propoxyphenyl)-4-(3,4-methylenedioxybenzyl)aminoquinazoline ##STR145##

molecular formula; C₂₅ H₂₃ N₃ O₃ (413)

yield (%); 15

m.p. (°C.); 130˜131

Mass; 414 (M+1)⁺

NMR δ (CDCl₃); 0.96 (3H, t, J=7.2Hz), 1.71˜1.77 (2H, m), 4.00 (2H, t, J=6.4Hz), 4.83 (2H, s), 5.95 (2H, s), 6.77˜7.93 (12H, m)

Example 85 4-(3,4-Methylenedioxybenzamido)-6,7,8-trimethoxyquinazoline ##STR146##

molecular formula; C₁₉ H₁₇ N₃ O₆

yield (%); 13

m.p. (°C.); 190˜192

Mass; 384 (M+H)⁺

NMR δ (CDCl₃); 4.10 (6H, s), 4.12 (3H, s), 6.07 (2H, s), 6.91 (1H, d, J=8.0Hz), 7.86 (1H, s), 7.90 (1H, s), 8.06 (1H, d, J=8.0Hz), 8.18 (1H, s)

Example 86 4-(3,4-Methylenedioxybenzyl)oxy-6,7,8-trimethoxyquinazoline ##STR147##

molecular formula; C₁₉ H₁₈ N₂ O₆

yield (%); 49

m.p. (°C.); 141˜142

Mass; 371 (M+H)⁺

NMR δ (CDCl₃); 3.97 (3H, s), 4.05 (3H, s), 4.13 (3H, s), 5.53 (2H, s), 5.99 (2H, s), 6.84 (1H, d, J=8.0Hz), 7.00 (1H, dd, J=8.0Hz, 2.0Hz), 7.02 (1H, d, J=2.0Hz), 7.20 (1H, s), 8.74 (1H, s)

Example 87 4-(3,4-Methylenedioxybenzyl)oxy-6-methylthioquinazoline ##STR148##

molecular formula; C₁₇ H₁₄ N₂ O₃ Cl

yield (%); 69

m.p. (°C.); 104˜105

Mass; 327 (M+H)⁺

NMR δ (CDCl₃); 2.59 (3H, s), 5.56 (2H, s), 6.00 (2H, s), 6.85 (1H, d, J=8.0Hz), 7.01 (1H, dd, J=8.0Hz, 1.6Hz), 7.03 (1H, d, J=1.6Hz), 7.72 (1H, dd, J=8.8Hz, 1.6Hz), 7.88 (1H, d, J=8.8Hz), 7.89 (1H, d, J=1.6Hz), 8.78 (1H, s)

Example 88 2,4,6-Trimethoxyquinazoline ##STR149##

5.0 g (0.022 mol) of 2,4-dichloro-6-methoxyquinazoline was suspended in 150 ml of methanol, followed by the gradual addition of 3.5 g of sodium hydride. The obtained mixture was heated under reflux. After several hours, the reaction mixture was concentrate under a reduced pressure, followed by the addition of water. The crystalline precipitate thus formed was recovered by filtration, washed with water and air-dried to give 4.8 g of the title compound as a crude yellow crystal.

m.p.; 143˜144

Mass; 221 (M+1)₊

NMR δ (CDCl₃); 3.90 (3H, s), 4.08 (3H, s), 4.18 (3H, s), 7.36 (1H, d, J=2.8Hz), 7.39 (1H, dd, J=8.8Hz, 2.8Hz), 7.67 (1H, d, J=2.8Hz)

Example 89 2,6-Dimethoxy-4-(3,4-methylenedioxybenzyl)aminoquinazoline ##STR150##

3.75 g (24.8 mmol) of piperonylamine was added to a solution of 2.00 g (8.26 mmol) of the 2,4,6-trimethoxyquinazoline prepared in Example 88 in dimethyl sulfoxide (15 ml). The obtained mixture was stirred under heating at 150° to 160° C. After one hour, the reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 0.50 g of the title compound as a pale-yellow crystal.

molecular formula; C₁₈ H₁₇ N₃ O₄

yield (%); 18

m.p. (°C.); 166˜167

Mass; 340 (M+1)⁺

NMR δ (CDCl₃); 3.89 (3H, s), 4.03 (3H, s), 4.77 (2H, d, J=5.2Hz), 5.94 (2H, s), 6.76 (1H, d, J=8.0Hz), 6.89 (1H, dd, J=8.0Hz, 1.2Hz), 6.93 (1H, d, J=1.2Hz), 7.29 (1H, dd, J=8.8Hz, 2.8Hz), 7.32 (1H, brs), 7.59 (1H, d, J=8.8Hz)

Example 90 2,4-Bisbenzyloxy-6-methoxyquinazoline ##STR151##

3 ml of benzyl alcohol was dissolved in 50 ml of tetrahydrofuran, followed by the addition of 1.0 g of sodium hydride. The obtained mixture was stirred at 40° to 50° C. for 30 minutes, followed by the addition of 2.50 g (0.0109 mol) of 2,4-dichloro-6-methoxyquinazoline. The obtained mixture was heated under reflux for several hours, followed by the addition of water. The obtained mixture was extracted with chloroform and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent. The obtained crystalline residue was recrystallized from chloroform/n-hexane to give 3.84 g of the title compound as a yellow crystal.

yield (%); 95

m.p. (°C.); 144˜145

Mass; 373 (M+1)⁺

NMR δ (CDCl₃); 3.87 (3H, s), 5.53 (2H, s), 5.62 (2H, s), 7.31˜7.55 (12H, m), 7.70 (1H, d, J=8.8Hz)

Example 91 2-Benzyloxy-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline ##STR152##

1.25 g (8.27 mmol) of piperonylamine was added to a solution of 1.00 g (2.69 mmol) of the 2,4-bisbenzyloxy-6-methoxyquinazoline prepared in Example 90 in dimethyl sulfoxide (10 ml). The obtained mixture was stirred at 160° to 180° C. After one hour, the reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 0.20 g of the title compound as a colorless needle.

molecular formula; C₂₄ H₂₁ N₃ O₄

yield (%); 18

m.p. (°C.); 163˜164

Mass; 416 (M+H)⁺

NMR δ (CDCl₃); 3.86 (3H, s), 4.75 (2H, d, J=5.2Hz), 5.49 (2H, s), 5.68 (1H, brs), 5.96 (2H, s), 6.79 (1H, d, J=8.0Hz), 6.84˜6.87 (3H, m), 7.28˜7.36 (4H, m), 7.51˜7.53 (2H, m), 7.63 (1H, d, J=9.2Hz)

Example 92 2,6-Dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline ##STR153##

A mixture comprising 3.6 g of 2,4,6-trichloroquinazoline, 2.4 g of piperonylamine, 1.6 g of triethylamine and 50 ml of isopropyl alcohol was heated under reflux for 1.5 hours and hot-filtered to give 5.2 g of the title compound as a filter cake.

molecular formula; C₁₆ H₁₁ N₃ O₂ Cl₂

yield (%); 98

m.p. (°C.); 215

Mass; 349 (M+1)⁺

NMR δ (DMSO-D₆); 4.61 (2H, s), 5.97 (2H, s), 6.85 (2H, s), 6.95 (1H, s), 7.63 (1H, d, J=8.8Hz), 7.80 (1H, dd, J=8.8Hz, 2.4Hz), 8.45 (1H, d, J=2.4Hz), 9.24 (1H, br)

Example 93 2-Chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR154##

35 ml of isopropyl alcohol, 900 mg of triethylamine and 1.35 g of piperonylamine were added to 2 g of 2,4-dichloro-6-cyanoquinazoline. The obtained mixture was heated under reflux for 1.5 hours and hot-filtered to recover a precipitate. Thus, 2.4 g of the title compound was obtained.

molecular formula; C₁₇ H₁₁ N₄ O₂ Cl

yield (%); 79

m.p. (°C.); 284˜286 (dec.)

Mass; 339 (M+1)⁺

NMR δ (DMSO-d₆); 4.63 (2H, d, J=5.6Hz), 5.97 (2H, s), 6.86 (2H, s), 6.97 (1H, s), 7.72 (1H, d, J=8.4Hz), 8.10 (1H, dd, J=8.4Hz, 1.8Hz), 8.90 (1H, d, J=1.8Hz), 9.50 (1H, br)

Example 94 2-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline ##STR155##

3.9 g of 3-chloro-4-methoxybenzylamine, 3.97 g of triethylamine and 200 ml of 2-propanol were added to 4 g of 2,4-dichloro-6-cyanoquinazoline. The obtained mixture was refluxed for 30 minutes, cooled to room temperature and filtered to recover a crystalline precipitate. The precipitate was washed with water and chloroform successively to give 5.563 g of the title compound.

molecular formula; C₁₇ H₁₂ N₄ OCl₂

yield (%); 87

m.p. (°C.); 264˜266

Mass m/e; 359 (M+1)

NMR δ (CDCl₃); 3.90 (3H, s), 4.73 (2H, d, J=5.2Hz), 6.92 (1H, d, J=8.4), 7.33 (1H, dd, J=8.4Hz, 2.0Hz), 7.45 (1H, d, J=2.0Hz), 7.74 (1H, d, J=8.4Hz), 7.83 (1H, dd, J=8.4Hz, 1.6Hz), 8.78 (1H, d, J=1.6Hz), 8.85 (1H, brs)

Examples 95 to 105

The following compounds were prepared in a similar manner to those of Examples 88 to 94.

Example 95 2-Chloro-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR156##

molecular formula; C₁₉ H₁₈ N₃ O₅ Cl

yield (%); 50

m.p. (°C.); 193˜194

Mass; 404 (M+H)⁺

NMR δ (CDCl₃); 3.94 (3H, s), 4.03 (3H, s), 4.10 (3H, s), 4.75 (2H, d, J=5.2Hz), 5.65 (1H, brs), 5.98 (2H, s), 6.59 (1H, s), 6.81 (1H, d, J=8.0Hz), 6.89 (1H, d, J=8.0Hz), 6.91 (1H, s)

Example 96 2-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR157##

molecular formula; C₁₉ H₁₉ C₁₂ N₃ O₄

yield (%); 45

m.p. (°C.); 199˜200

Mass; 424 (M+1)⁺

NMR δ (CDCl₃); 3.89 (3H, s), 3.95 (3H, s), 4.02 (3H, s), 4.08 (3H, s), 4.76 (2H, d, J=5.6Hz), 6.39 (1H, brs), 6.83 (1H, s), 6.89 (1H, d, J=8.3Hz), 7.31 (1H, dd, J=8.4Hz, 2.0Hz), 7.40 (1H, d, J=2.0Hz)

Example 97 2-Chloro-4-(3,4-methylenedioxybenzyl)amino-6,7-dimethoxyquinazoline ##STR158##

molecular formula; C₁₈ H₁₆ N₃ O₄ Cl

yield (%); 97

m.p. (°C.); 177˜178

Mass; 374 (M+H)⁺

NMR δ (CDCl₃); 3.95 (3H, s), 3.97 (3H, s), 4.75 (2H, d, J=5.2Hz), 5.74 (1H, brt, J=5.2Hz), 5.97 (2H, s), 6.80 d, J=8.0Hz), 6.81 (1H, s), 6.88 (1H, dd, J=8.0Hz, 2.0Hz), 6.91 (1H, d, J=2.0Hz), 7.14 (1H, s)

Example 98 2-Chloro-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline ##STR159##

molecular formula; C₁₇ H₁₄ N₃ O₃ Cl

yield (%); 80

m.p. (°C.); 202˜203

Mass; 344 (M+1)⁺

NMR δ (CDCl₃); 3.91 (3H, s), 4.77 (2H, d, J=5.6Hz), 5.94 (2H, s), 6.76 (1H, d, J=8.0Hz), 6.91 (1H, dd, J=8.0Hz, 1.6Hz), 6.95 (1H, d, J=1.6Hz), 7.35 (1H, dd, J=9.2Hz, 2.8Hz), 7.46 (1H, brd, J=2.8Hz), 7.69 (1H, d, J=9.2Hz), 7.90 (1H, brs)

Example 99 2-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-methoxyquinazoline ##STR160##

molecular formula; C₁₇ H₁₅ N₃ O₂ Cl₂

yield (%); 88

m.p. (°C.); 171˜172

Mass; 364 (M+1)⁺

NMR δ (DMSO); 3.83 (3H, s), 3.88 (3H, s), 4.68 (2H, d, J=5.6Hz), 7.13 (1H, d, J=8.8Hz), 7.33 (1H, dd, J=2.4Hz, 8.8Hz), 7.44 (1H, dd, J=2.8Hz, 9.2Hz), 7.46 (1H, d, J=2.4Hz), 7.58 (1H, d, J=9.2Hz), 7.72 (1H, d, J=2.8Hz), 9.05 (1H, t, J=5.6Hz)

Example 100 2,6-Dichloro-4-benzylaminoquinazoline ##STR161##

molecular formula; C₁₅ H₁₁ N₃ Cl₂

yield (%); 77

m.p. (°C.); 227˜228

NMR δ (CDCl₃); 4.85 (2H, d, J=5.2Hz), 5.97 (1H, brs), 7.33˜7.43 (5H, m), 7.62 (1H, d, J=2.0Hz), 7.68 (1H, dd, J=8.8Hz, 2.0Hz), 7.74 (1H, d, J=8.8Hz)

Example 101 2,6-Dichloro-4-[2-(3,4-methylenedioxyphenyl)ethyl]aminoquinazoline ##STR162##

molecular formula; C₁₇ H₁₃ N₃ O₂ Cl₂

yield (%); 71

m.p. (°C.); 228˜229

NMR δ (DMSO-d₆); 2.88 (2H, t, J=7.4Hz), 3.68 (2H, m), 5.96 (2H, s), 6.70 (1H, dd, J=8.0Hz, 1.6Hz), 6.81 (1H, d, J=8.0Hz), 6.87 (1H, d, J=1.6Hz), 7.63 (1H, d, J=8.8Hz), 7.80 (1H, dd, J=8.8Hz, 2.0Hz), 8.40 (1H, d, J=2.0Hz), 8.86 (1H, d, J=5.2Hz)

Example 102 2,6-Dichloro-4-(3-chloro-4-methoxybenzyl)aminoquinazoline ##STR163##

molecular formula; C₁₆ H₁₂ N₃ OCl

yield (%); 93

m.p. (°C.); 207˜208

Mass m/e; 368 (M+1)

NMR δ (CDCl₃); 3.90 (3H, s), 4.73 (2H, d, J=5.6Hz), 6.91 (1H, d, J=8.4Hz), 7.32 (1H, d, J=8.4Hz, 2.0Hz), 7.45 (1H, d, J=2.0Hz), 7.62 (1H, dd, J=8.8Hz, 2.0Hz), 7.66 (1H, d, J=8.8Hz), 8.07 (1H, brs), 8.16 (1H, d, J=2.0Hz)

Example 103 2,6-Dichloro-4-(benzimidazol-5-yl)methylaminoquinazoline ##STR164##

molecular formula; C₁₆ H₁₁ N₅ Cl₂ (344.205)

yield (%); 81

m.p. (°C.); >290

Mass; 344 (M+1)⁺

NMR δ (DMSO); 4.85 (2H, d, J=6.0Hz), 7.25 (1H, dd, J=1.6Hz, 6.4Hz), 7.57 (1H, d, J=6.4Hz), 7.60 (1H, s), 7.66 (1H, d, J=8.8Hz), 7.83 (1H, dd, J=2.0Hz, 8.8Hz), 8.21 (1H, s), 8.44 (1H, brs), 8.52 (1H, d, J=2.0Hz), 9.37 (1H, t, J=6.0Hz)

Example 104 2-Chloro-4-(benzimidazol-5-yl)methylamino-6-cyanoquinazoline ##STR165##

molecular formula; C₁₇ H₁₁ N₆ Cl (334.5)

yield (%); 58

m.p. (°C.); >290

Mass; 335 (M+1)⁺

NMR δ (DMSO-d₆); 4.81 (2H, s), 7.21˜7.68 (3H, m), 7.73 (1H, d, J=8.8Hz), 8.10 (1H, d, J=8.8Hz), 8.17 (1H, s), 8.91 (1H, s), 9.55 (1H, br)

Example 105 2-Chloro-4-[N-(2-hydroxyethyl)-(3,4-methylenedioxybenzyl)amino]-6,7,8-trimethoxyquinazoline ##STR166##

molecular formula; C₂₁ H₂₂ N₃ O₆ Cl

yield (%); 55

Mass; 448 (M+H)⁺

NMR δ (CDCl₃); 3.38 (3H, s), 3.88 (2H, t, J=4.4Hz), 4.01 (2H, t, J=4.4Hz), 4.03 (3H, s), 4.07 (3H, s), 4.92 (2H, s), 6.01 (2H, s), 6.88˜6.91 (3H, m), 7.00 (1H, s)

Example 106 2-Formyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR167##

0.50 g (0.0013 mol) of 2-ethoxycarbonyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was dissolved in a solvent mixture comprising 20 ml of methylene chloride and 20 ml of tetrahydrofuran. 2.6 ml of a 1.0M solution of diisobutylaluminum hydride in toluene was dropped into the solution prepared above at -78° C. under stirring. The obtained mixture was stirred at -78° C. for several hours, followed by the addition of 20 ml of methanol. The obtained mixture was distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate/n-hexane to give 0.23 g of the title compound as a pale-yellow crystal.

yield (%); 52

m.p. (°C.); 200˜202 (dec.)

Mass; 342 (M+1)⁺

NMR δ (CDCl₃); 4.86 (2H, d, J=5.2Hz), 5.98 (2H, s), 6.81 (1H, d, J=7.6Hz), 6.90 (1H, d, J=7.6Hz), 6.92 (1H, s), 7.72 (1H, d, J=2.0Hz), 7.77 (1H, dd, J=8.8Hz, 2.0Hz), 8.01 (1H, d, J=8.8Hz), 10.05 (1H, s)

Example 107 2-Ethoxycarbonyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR168##

2.72 g (0.0100 mol) of 2-ethoxycarbonyl-4,6-dichloroquinazoline, 1.75 g (0.0116 mol) of piperonylamine and 1.60 g (0.0151 mol) of sodium carbonate were mixed with 100 ml of isopropyl alcohol. The obtained mixture was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography and recrystallized from chloroform/n-hexane to give 3.56 g of the title compound as a colorless needle.

molecular formula; C₁₉ H₁₆ N₃ O₄ Cl

yield (%); 92

m.p. (°C.); 212˜218

Mass; 386 (M+H)⁺

NMR δ (CDCl₃); 1.49 (3H, t, J=7.2Hz), 1.54 (2H, q, J=7.2Hz), 4.83 (2H, d, J=5.6Hz), 5.96 (1H, brs), 5.97 (2H, s), 6.80 (1H, d, J=8.0Hz), 6.91 (1H, dd, J=8.0Hz, 1.6Hz), 6.97 (1H, J=1.6Hz), 7.70 (1H, d, J=2.0Hz), 7.72 (1H, dd, J=8.8Hz, 2.0Hz), 8.00 (1H, d, J=8.8Hz)

Examples 108 to 111

The following compounds were prepared in a similar manner to that of Examples 106 or 107.

Example 108 2-Ethoxycarbonyl-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazoline ##STR169##

molecular formula; C₁₉ H₁₇ N₃ O₃ Cl₂ yield(%); 88 m.p.(°C.); 185-186 Mass; 406 (M+1)⁺ NMR δ (CDCl₃); 1.49 (3H, t, J=7.2 Hz), 3.90 (3H, s), 4.54 (2H, q, J=7.2 Hz), 4.84 (2H, d, J=5.2 Hz), 6.09 (1H, brs), 6.90 (1H, d, J=8.4 Hz), 7.33 (1H, dd, J=8.4 Hz, 2.4 Hz), 7.48 (1H, d, J=2.4 Hz), 7.72 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.74 (1H, d, J=2.4 Hz), 7.99 (1H, d, J=8.8 Hz)

EXAMPLE 109 2-Ethoxycarbonyl-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR170##

molecular formula; C₂₂ H₂₃ N₃ O₇ yield (%); quantitative m.p. (°C.) ; 168-165 (dec.) Mass; 442 (M+1)⁺ NMR δ (CDCl₃); 1.45 (3H, t, J=7.2 Hz), 3.94 (3H, s), 4.02 (3H, s), 4.18 (3H, s), 4.46 (2H, q, J=7.2 Hz), 4.80 (2H, d, J=5.2 Hz), 5.89 (1H, brt, J=5.2 Hz), 5.94 (2H, s), 6.74 (1H, d, J=7.6 Hz), 6.76 (1H, s), 6.86 (1H, dd, J=7.6 Hz, 1.6 Hz), 6.94 (1H, d, J =1.6 Hz)

EXAMPLE 110 2-Ethoxycarbonyl-4-(3-chloro-4-methoxybenzyl)amino-6-methoxyquinazoline ##STR171##

molecular formula; C₂₀ H₂₀ N₃ O₄ Cl yield(%); 73 m.p.(°C.); 192-193 Mass; 402 (M+1)⁺ NMR δ (CDCl₃); 1.49 (3H, t, J=7.2 Hz), 3.90 (3H, s), 3.91 (3H, s), 4.53 (2H, q, J=7.2 Hz), 4.86 (2H, d, J=5.6 Hz), 5.90 (1H, brt, J=5.6 Hz), 6.90 (1H, d, J=8.4 Hz), 6.96 (1H, d, J=2.4 Hz), 7.36 (1H, dd, J=8.4 Hz, 2.4 Hz), 7.44 (1H, dd, J=9.2 Hz, 2.4 Hz), 7.49 (1H, d, J=2.4 Hz), 8.00 (1H, d, J=9.2 Hz)

EXAMPLE 111 2-Ethoxycarbonyl-4-(benzimidazol-5-ylmethyl)amino-6-methoxyquinazoline ##STR172##

molecular formula; C₂₀ H₁₉ N₅ O₃ yield(%); 48 m.p.(°C.); 244-245 (dec.) Mass; 378 (M+1)⁺ NMR δ (DMSO-d₆); 1.35 (3H, t, J=7.2 Hz), 3.90 (3H, s), 4.33 (2H, q, J=7.2 Hz), 4.94 (2H, d, J=6.0 Hz), 7.31 (1H, d, J=8.0 Hz), 7.47 (1H, dd, J=8.8 Hz, 2.8 Hz), 7.53 (1H, d, J=8.0 Hz), 7.65 (1H, brs), 7.77 (1H, d, J=8.8 Hz), 7.78 (1H, s), 8.17 (1H, s), 8.89 (1H, brt, J=6.0 Hz)

EXAMPLE 112 (E)-2-(2-Ethoxycarbonyl-1-propenyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR173##

0.52 g (0.013 mol) of sodium hydride was added to a solution of 4.00 g (0.0117 mol) of 2-formyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 250 ml of tetrahydrofuran. 2.8 ml (0.013 mol) of triethyl 2-phosphonopropionate was dropped into the mixture prepared above under stirring and cooling with ice. The mixture thus prepared was stirred under cooling with ice for a while, heated to room temperature and stirred for additional one hour, followed by the addition of 1.5 ml of 8M hydrochloric acid/ethanol. The obtained mixture was passed through a small amount of silica gel and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from chloroform/n-hexane to give 2.00 g of the title compound.

molecular formula; C₂₂ H₂₀ N₃ O₄ Cl yield(%); 40 m.p.(°C.); 179-180 (dec.) Mass; 426 (M+1)⁺ NMR δ (CDCl₃); 1.35 (3H, t, J=7.2 Hz), 2.50 (3H, d, J=1.6 Hz), 4.29 (2H, q, J=7.2 Hz), 4.78 (2H, d, J=5.2 Hz), 5.77 (1H, brt, J=5.2 Hz), 5.97 (2H, s), 6.81 (1H, d, J=8.0 Hz), 6.87 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.89 (1H, d, J=1.6 Hz), 7.62 (1H, J=1.6 Hz), 7.64 (1H, d, J=2.0 Hz), 7.68 (1H, J=8.8 Hz, 2.0 Hz), 7.81 (1H, d, J=8.8 Hz)

EXAMPLES 113 TO 119

The following compounds were prepared in a similar manner to that of Example 112.

EXAMPLE 113 (Z)-2-(2-Ethoxycarbonyl-1-propenyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR174##

molecular formula; C₂₂ H₂₀ N₃ O₄ Cl yield(%); 13 amt. of product (g); 0.64 m.p.(°C.); 162-164 (dec.) Mass; 426 (M+1)⁺ NMR δ (CDCl₃); 1.20 (3H, t, J=7.2 Hz), 2.17 (3H, d, J=1.6 Hz), 4.21 (2H, q, J=7.2 Hz), 4.70 (2H, d, J=4.8 Hz), 5.64 (1H, brs), 5.97 (2H, s), 6.53 (1H, q, J=1.6 Hz), 6.81 (1H, d, J=7.6 Hz), 6.85 (1H, dd, J =7.6 Hz, 1.6 Hz), 6.87 (1H, d, J=1.6 Hz), 7.58 (1H, d, J=2.4 Hz), 7.62 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.71 (1H, d, J=8.8 Hz)

EXAMPLE 113 (E)-2-(2-Ethoxycarbonylvinyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR175##

molecular formula; C₂₁ H₁₈ N₃ O₄ Cl yield(%); 67 m.p.(°C.); 195-196 Mass; 412 (M+1)⁺ NMR δ (CDCl₃); 1.35 (3H, t, J=7.2 Hz), 4.29 (2H, q, J=7.2 Hz), 4.80 (2H, d, J=5.2 Hz), 5.77 (1H, brs), 5.97 (2H, s), 6.81 (1H, d, J=7.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.90 (1H, s), 7.21 (1H, d, J=15.6 Hz), 7.64 (1H, d, J =2.0 Hz), 7.66 (1H, d, J=15.6 Hz), 7.68 (1H, dd, J=9.2 Hz, 2.0 Hz), 7.82 (1H, d, J=9.2 Hz)

EXAMPLE 115 (E)-2-(2-Ethoxycarbonylvinyl)-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazoline ##STR176##

molecular formula; C₂₁ H₁₉ N₃ O₄ Cl₂ yield(%); 74 m.p.(°C.); 211-212 Mass; 432 (M+1)⁺ NMR δ (CDCl₃); 1.35 (3H, J=7.2 Hz), 3.89 (3H, s), 4.28 (2H, q, J=7.2 Hz), 4.79 (2H, d, J=5.6 Hz), 6.91 (1H, d, J=8.4 Hz), 7.16 (1H, d, J=15.6 Hz), 7.33 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.46 (1H, d, J=2.0 Hz), 7.62 (1H, d, J=15.6 Hz), 7.64 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.75 (1H, d, J =8.8 Hz), 7.77 (1H, brs), 8.16 (1H, d, J =2.4 Hz)

EXAMPLE 116 (E)-2-(2-Ethoxycarbonyl-1-propenyl)-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazoline ##STR177##

molecular formula; C₂₂ H₂₁ N₃ O₃ Cl yield(%); 54 m.p.(°C.); 154-155 Mass; 446 (M+1)⁺ NMR δ (CDCl₃); 1.35 (3H, t, J=7.2 Hz), 2.48 (3H, d, J=1.6 Hz), 3.91 (3H, s), 4.29 (2H, q, J=7.2 Hz), 4.80 (2H, d, J=5.2 Hz), 5.82 (1H, brt, J=5.2 Hz), 6.92 (1H, d, J=8.8 Hz), 7.27 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.42 (1H, d, J=2.0 Hz), 7.62 (1H, q, J=1.6 Hz), 7.67 (1H, d, J=2.4 Hz), 7.69 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.82 (1H, d, J=8.8 Hz)

EXAMPLE 117 (Z)-2-(2-Ethoxycarbonyl-1-propenyl)-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazoline ##STR178##

molecular formula; C₂₂ H₂₁ N₃ O₄ Cl ₂ yield(%); 11 m.p.(°C.); 141-142 Mass; 446 (M+1)⁺ NMR δ (CDCl₃); 1.19 (3H, t, J=7.2 Hz), 2.17 (3H, d, J=1.6 Hz), 3.91 (3H, s), 4.19 (2H, q, J=7.2 Hz), 4.73 (2H, d, J=5.2 Hz), 5.69 (1H, brt, J=5.2 Hz), 6.53 (1H, q, J=1.6 Hz), 6.92 (1H, d, J=8.4 Hz), 7.26 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.40 (1H, d, J=2.0 Hz), 7.60 (1H, d, J=2.0 Hz), 7.63 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.71 (1H, d, J=8.8 Hz)

EXAMPLE 118 (E)-2-(2-Ethoxycarbonyl-1-propenyl)-4-(3,4-methylenedioxybenzyl)amino-6,7,8-tribethoxyquinazoline ##STR179##

molecular formula; C₂₅ H₂₇ N₃ O₇ yield(%); 51 m.p.(°C.); 175-176 Mass; 482 (M+1) ⁺ NMR δ (CDCl₃); 1.35 (3H, t, J=7.2 Hz), 2.52 (3H, d, J=1.6 Hz), 3.95 (3H, s), 4.04 (3H, s), 4.14 (3H, s), 4.28 (2H, q, J=7.2 Hz), 4.80 (2H, d, J=5.2 Hz), 5.60 (1H, brt, J=5.2 Hz), 5.96 (2H, s), 6.67 (1H, s), 6.80 (1H, d, J=8.0 Hz), 6.87 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.90 (1H, d, J=1.6 Hz), 7.69 (1H, q, J=1.6 Hz)

EXAMPLE 119 (Z)-2-(2-Ethoxycarbonyl-1-propenyl)-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR180##

molecular formula; C₂₅ H₂₇ N₃ O₇ yield(%); 11 m.p. (°C.); 157-158 (dec.) Mass; 482 (M+1)⁺ NMR δ (CDCl₃); 1.19 (3H, t, J=7.2 Hz), 2.16 (3H, s), 3.92 (3H, s), 4.02 (3H, s), 4.09 (3H, s), 4.21 (2H, q, J=7.2 Hz), 4.72 (2H, d, J=5.2 Hz), 5.43 (1H, brs), 5.96 (2H, s), 6.59-6.61 (2H, m), 6.80 (1H, d, J =8.0 Hz), 6.86-6.89 (2H, m)

EXAMPLE 120 (E)-2-(2-Carboxy-1-propenyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR181##

1.00 g (0.0023 mol) of (E)-2-(2-ethoxycarbonylpropenyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was dissolved in a mixture comprising 5 ml of tetrahydrofuran and 20 ml of ethanol, followed by the addition of 20 ml of a 1N aqueous solution of sodium hydroxide. The obtained mixture was stirred at room temperature for several hours, neutralized with 20 ml of 1N hydrochloric acid and concentrated under a reduced pressure. The crystal thus formed was recovered by filtration, washed with water and air-dried to give 0.85 g of the title compound.

molecular formula; C₂₀ H₁₆ N₃ O₄ Cl yield(%); 91 m.p.(°C.); 145-146 Mass; 398 (M+1)⁺ NMR δ (DMSO-d₆); 2.36 (3H, d, J=1.6 Hz), 4.70 (2H, d, J=5.6 Hz), 5.97 (2H, s), 6.85 (2H, s), 6.95 (1H, s), 7.34 (1H, q, J=1.6 Hz), 7.72 (1H, d, J=8.8 Hz), 7.79 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.46 (1H, d, J=2.0 Hz), 8.86 (1H, brt, J=5.6 Hz)

EXAMPLES 121 TO 128

The following compounds were prepared in a similar manner to that of Example 120.

EXAMPLE 121 2-Carboxy-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR182##

molecular formula; C₁₇ H₁₂ N₃ O₄ Cl yield(%); quantitative m.p.(°C.); 240 (dec.) Mass; 402 (M-1+2Na)⁺ NMR δ (DMSO-d₆); 4.71 (2H, d, J=5.6 Hz), 5.96 (2H, s), 6.83 (1H, d, J=8.0 Hz), 6.89 (1H, dd, J=8.0 Hz, 1.2 Hz), 7.06 (1H, d, J=1.2 Hz), 7.75 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.90 (1H, d, J=8.8 Hz), 8.48 (1H, d, J=2.4 Hz), 8.82 (1H, brt, J=5.6 Hz)

EXAMPLE 122 (E)-2-(2-Carboxyvinyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR183##

molecular formula; C₁₉ H₁₄ N₃ O₄ Cl yield(%); 43 m.p.(°C.); 114-115 Mass; 428 (M-1+2Na)⁺ NMR δ (DMSO-d₆); 4.71 (2H, d, J=5.6 Hz), 5.96 (2H, s), 6.84 (1H, d, J=8.0 Hz), 6.90 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.99 (1H, d, J=1.6 Hz), 7.02 (1H, d, J=15.6 Hz), 7.23 (1H, d, J=15.6 Hz), 7.73 (1H, d, J=9.2 Hz), 7.78 (1H, dd, J=9.2 Hz, 2.0 Hz), 8.44 (1H, d, J=2.0 Hz), 8.89 (1H, brt, J=5.6 Hz)

EXAMPLE 123 (Z)-2-(2-carboxy-1-propenyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR184##

molecular formula; C₂₀ H₁₆ N₃ O₄ Cl yield(%); quantitative m.p.(°C.); 195-196 Mass; 398 (M+1)⁺ NMR δ (DMSO-d₆); 2.10 (3H, d, J=1.6 Hz), 4.70 (2H, d, J=5.6 Hz), 5.97 (2H, s), 6.56 (1H, d, J=1.6 Hz), 6.86 (1H, d, J=8.0 Hz), 6.91 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.00 (1H, d, J=1.6 Hz), 7.65 (1H, d, J=9.2 Hz), 7.81 (1H, dd, J=9.2 Hz, 2.4 Hz), 8.46 (1H, d, J=2.4 Hz), 8.99 (1H, brt, J=5.6 Hz)

EXAMPLE 124 (E)-2-(2-Carboxyvinyl)-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazoline ##STR185##

molecular formula; C₁₉ H₁₅ N₃ O₃ Cl₂ yield(%); quantitative m.p.(°C.); 109-110 Mass; 448 (M-1+2Na)⁺ NMR δ (DMSO-d₆); 3.81 (3H, s), 4.73 (2H, d, J=5.6 Hz), 6.95 (1H, d, J=15.6 Hz), 7.05 (1H, d, J=15.6 Hz), 7.08 (1H, d, J=8.4 Hz), 7.37 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.48 (1H, d, J=2.0 Hz), 7.68 (1H, d, J=8.8 Hz), 7.73 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.42 (1H, d, J=2.0 Hz), 8.91 (1H, brt, J=5.6 Hz)

EXAMPLE 125 (E)-2-(2-Carboxy-1-propenyl)-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazoline ##STR186##

molecular formula; C₂₀ H₁₇ N₃ O₃ Cl₂ yield(%); quantitative m.p. (°C.); 151-152 Mass; 462 (M-1+2Na) NMR δ (DMSO-d₆); 2.33 (3H, d, J=1.2 Hz), 3.82 (3H, s), 4.72 (2H, d, J=5.6 Hz), 7.09 (1H, d, J=8.4 Hz), 7.20 (1H, d, J=1.2 Hz), 7.32 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.44 (1H, d, J=2.0 Hz), 7.67 (1H, d, J=8.8 Hz), 7.74 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.43 (1H, d, J=2.4 Hz), 8.87 (1H, brt, J=5.6 Hz)

EXAMPLE 126 (Z)-2-(2-Carboxy-1-propenyl)-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazoline ##STR187##

molecular formula; C₂₀ H₁₇ N₃ O₃ Cl₂ yield(%); quantitative m.p.(°C.); 207-208 (dec.) Mass; 418 (M+1)⁺ NMR δ (DMSO-d₆); 2.10 (3H, d, J=1.4 Hz), 3.83 (3H, s), 4.72 (2H, d, J=5.2 Hz), 6.54 (1H, d, J=1.4 Hz), 7.10 (1H, d, J=8.4 Hz), 7.38 (1H, dd, J=8.4 Hz, 2.4 Hz), 7.49 (1H, d, J=2.4 Hz), 7.65 (1H, d, J=8.8 Hz), 7.81 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.44 (1H, d, J=2.4 Hz), 8.95 (1H, brt, J=5.2 Hz)

EXAMPLE 127 (E)-2-(2-Carboxy-1-propenyl)-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR188##

molecular formula; C₂₃ H₂₃ N₃ O₇ yield(%); 91 m.p.(°C.); 200-201 (dec.) Mass; 454 (M+1)⁺ NMR δ (DMSO-d₆); 2.38 (3H, s), 3.89 (3H, s), 3.92 (3H, s), 4.01 (3H, s), 4.71 (2H, d, J=5.6 Hz), 5.97 (2H, s), 6.85 (2H, s), 6.93 (1H, s), 7.37 (1H, s), 7.53 (1H, s), 8.53 (2H, brt, J=5.6 Hz), 12.55 (1H, brs)

EXAMPLE 128 (Z)-2-(2-Carboxy-1-propenyl)-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR189##

molecular formula; C₂₃ H₂₃ N₃ O₇ yield(%); 90 m.p.(°C.); 237-238 (dec.) Mass; 484 (M+1)⁺ NMR δ (DMSO-d₆); 2.11 (3H, d, J=1.2 Hz), 3.92 ((3H, s), 3.93 (3H, s), 3.94 (3H, s), 4.76 (2H, d, J=5.6 Hz), 5.98 (2H, s), 6.8-6.9 (3H, m), 6.97 (1H, s), 7.61 (1H, s), 9.08 (1H, brt, J=5.6 Hz)

EXAMPLE 129 4-(α-Carboxy-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR190##

10 ml of ethanol, 5 ml of water and 20 mg of sodium hydroxide were added to 100 mg of 4-(α-ethoxycarbonyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was refluxed for 10 minutes and concentrated under a reduced pressure, followed by the addition of 20 ml of water. The obtained mixture was neutralized with 1N hydrochloric acid. The crystal thus precipitated was recovered by filtration. Thus, 45 mg of the title compound was obtained.

molecular formula; C₁₇ H₁₂ N₃ O₄ Cl yield (%); 49 m.p.(°C.); 235-236 Mass m/e; 358 (M+1) NMR δ (DMSO-d₆); 5.75 (1H, d, J=6.4 Hz), 6.01 (2H, s), 6.89 (1H, d, J=8.0 Hz), 7.00 (1H, d, J=8.0 Hz), 7.08 (1H, s), 7.70 (1H, d, J=8.8 Hz), 7.75 (1H, dd, J=1.6 Hz, 8.8 Hz), 8.49 (1H, s), 8.59 (1H, d, J=6.4 Hz), 8.70 (1H, d, J=1.6 Hz)

EXAMPLES 130 TO 131

The following compounds were prepared in a similar manner to that of Example 129.

EXAMPLE 130 4-[N-(Carboxymethyl)-(3,4-methylenedioxybenzyl)amino]-6,7,8-trimethoxyquinazoline ##STR191##

molecular formula; C₂₁ H₂₁ N₃ O₇ yield(%); 90 m.p.(°C.); 134-136 Mass; 428 (M+H)⁺ NMR δ (CDCl₃); 3.43 (3H, s), 4.06 (3H, s), 4.17 (3H, s), 4.62 (2H, s), 5.16 (2H, s), 6.03 (2H, s), 6.87 (1H, s), 6.91 (2H, s), 7.06 (1H, s), 8.87 (1H, s)

EXAMPLE 131 4-(3,4-Methylenedioxybenzyl)amino-6-carboxyquinazoline ##STR192##

molecular formula; C₁₇ H₁₃ N₃ O₄ yield(%); 98 m.p.(°C.); 247-248 (dec.) Mass; 324 (M+H)⁺ NMR δ (DMSO-d₆); 4.86 (2H, d, J=5.6 Hz), 5.99 (2H, s), 6.89 (1H, d, J=8.0 Hz), 6.92 (1H, d, J=8.0 Hz), 7.02 (1H, s), 7.92 (1H, d, J=8.8 Hz), 8.46 (1H, d, J=8.8 Hz), 8.96 (1H, s), 9.20 (1H, s), 10.88 (1H, brs)

EXAMPLE 132 4-(α-Carbamoyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR193##

20 ml of a 10% solution of ammonia in ethanol was added to 200 mg of 4-(α-ethoxycarbonyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was stirred at room temperature for 3 days. The crystal thus precipitated was recovered by filtration. Thus, 60 mg of the title compound was obtained.

molecular formula; C₁₇ H₁₃ N₄ O₃ Cl yield(%); 32 m.p.(°C.); 230-231 Mass m/e; 357 (M+1) NMR δ (CDCl₃ +DMSO-d₆); 5.96 (3H, m), 6.42 (1H, brs), 6.79 (1H, d, J=8.0 Hz), 7.09 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.14 (1H, d, J=1.6 Hz), 7.15 (1H, brs), 7.67 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.75 (1H, d, J=8.8 Hz), 8.28 (1H, d, J=2.0 Hz), 8.57 (1H, s)

EXAMPLES 133 AND 134

The following compounds were prepared in a similar manner to that of Example 132.

EXAMPLE 133 4-(3,4-Methylenedioxybenzyl)amino-6-carbamoylquinazoline ##STR194##

molecular formula; C₁₇ H₁₄ N₄ O₃ Mass; 323 (M+H)⁺ NMR δ (DMSO-d₆); 4.68 (2H, d, J=6.0 Hz), 5.97 (2H, s), 6.85 (1H, d, J=8.0 Hz), 6.88 (1H, d, J=8.0 Hz), 6.97 (1H, s), 7.55 (1H, brs), 7.70 (1H, d, J=8.4 Hz), 7.97 (1H, brs ), 8.18 (1H, dd, J=8.4 Hz, 1.6 Hz), 8.50 (1H, s), 8.84 (1H, d, J=1.6 Hz), 8.92 (1H, brt, J=6.0 Hz)

EXAMPLE 134 2-Carbamoyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR195##

molecular formula; C₁₇ H₁₃ ClN₄ O₃ yield(%); 71 m.p.(°C.); 245-247 (dec.) Mass; 857 (M+1) NMR δ (DMSO-d₆); 4.77 (2H, d, J=5.2 Hz), 5.97 (2H, s), 6.85 (1H, d, J=8.0 Hz), 6.92 (1H, d, J=8.0 Hz), 7.04 (1H, s), 7.66 (1H, brs), 7.83 (2H, m), 8.07 (1H, brs), 8.49 (1H, s), 8.99 (1H, brs)

EXAMPLE 135 4-(α-Hydroxymethyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR196##

10 ml of ethanol and 197 mg of sodium borohydride were added to 200 mg of 4-(α-ethoxycarbonyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was refluxed for 30 minutes, followed by the addition of 5 ml of water. The obtained mixture was concentrated under a reduced pressure, followed by the addition of 10 ml of water. The crystal thus precipitated was recovered by filtration. Thus, 30 mg of the title compound was obtained.

molecular formula; C₁₇ H₁₄ N₃ O₃ Cl yield(%); 17 m.p.(°C.); 204-205 Mass m/e; 344 (M+1) NMR δ (CDCl₃ (+DMSO-d₆)); 3.95 (2H, m), 5.43 (1H, q, J=4.4 Hz), 5.92 (1H, d, J=1.6 Hz), 5.93 (1H, d, J=1.6 Hz), 6.76 (1H, d, J=8.0 Hz), 6.90 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.95 (1H, d, J=1.6 Hz), 7.60 (1H, brs), 7.65 (1H, dd, J=8.4 Hz, 2.4 Hz), 7.74 (1H, d, J=8.4 Hz), 8.31 (1H, d, J=2.4 Hz), 8.53 (1H, s)

EXAMPLE 136 4-[(3,4-Methylenedioxybenzyl)amino-6-hydroxymethylquinazoline ##STR197##

The title compound was prepared in a similar manner to that of Example 135.

molecular formula; C₁₇ H₁₅ N₃ O₃ yield(%); 34 m.p.(°C.); 176-177 Mass m/e; 310 (M+1) NMR δ (DMSO-d₆); 4.62 (2H, d, J=5.6 Hz), 4.65 (2H, d, J=5.6 Hz), 5.36 (1H, t, J=5.6 Hz), 5.94 (2H, s), 6.82 (1H, s), 6.82 (1H, s), 6.92 (1H, s), 7.63 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=8.4 Hz), 8.20 (1H, s), 8.41 (1H, s), 8.74 (1H, t, J=5.6 Hz)

EXAMPLE 137 4-(3,4-Methylenedioxybenzyl)amino-6-methylsulfinylquinzoline ##STR198##

A solution of 1.20 g (6.95 mmol) of m-chloroperbenzoic acid in 30 ml of chloroform was dropped into a solution of 1.80 g (5.53 mmol) of 4-(3,4-methylenedioxybenzyl)amino-6-methylthioquinazoline in 100 ml of chloroform under cooling with ice and stirring. The obtained mixture was stirred under cooling with ice for several hours, washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and filtered. The filtrate was purified by silica gel column chromatography (ethyl acetate/acetone) and recrystallized from chloroform/n-hexane to give 1.51 g of the title compound as a pale-yellow crystal.

molecular formula; C₁₇ H₁₅ N₃ O₃ S yield(%); 80 m.p.(°C.); 154-155 Mass; 342 (M+H)⁺ NMR δ (CDCl₃); 2.75 (3H, s), 4.80 (2H, d, J=5.2 Hz), 5.96 (2H, s), 6.80 (1H, d, J=8.0 Hz), 6.89 (1H, d, J=8.0 Hz), 6.91 (1H, s), 7.06 (1H, brs), 7.64 (1H, d, J=8.8 Hz), 7.98 (1H, d, J=8.8 Hz), 8.43 (1H, s), 8.74 (1H, s)

EXAMPLE 138 4-(3,4-Methylenedioxybenzyl)amino-6-methylsulfonylquinazoline ##STR199##

A solution of 0.65 g (3.8 mmol) of m-chloroperbenzoic acid in 20 ml of chloroform was dropped into a solution of 1.00 g (2.93 mmol) of the 4-(3,4-methylenedioxybenzyl)amino-6-methylsulfinylquinazoline prepared in Example 137 under stirring at room temperature. The obtained mixture was stirred at room temperature for several hours, washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and filtered. The filtrate was purified by silica gel column chromatography (ethyl acetate) and recrystallized from chloroform/n-hexane to give 0.85 g of the title compound as a yellow crystal.

molecular formula; C₁₇ H₁₅ N₃ O₄ S yield(%); 81 m.p.(°C.); 192-193 Mass; 358 (M+H)⁺ NMR δ (CDCl₃); 3.13 (3H, s), 4.80 (2H, d, J=5.2 Hz), 5.95 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.91 (1H, d, J=8.0 Hz), 6.95 (1H, s), 8.05 (1H, d, J=8.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.72 (1H, s), 8.81 (1H, brs), 8.98 (1H, s)

EXAMPLE 139 2-Hydroxymethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline ##STR200##

1.5 g of 10% palladium/carbon powder was added to a solution of 1.26 g (2.93 mmol) of 2-benzyloxymethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline in an ethyl acetate/ethanol (20 ml-20 ml) mixture. The obtained mixture was stirred at room temperature in a stream of hydrogen for 24 hours and filtered through Celite. The filter cake was washed with hot ethyl acetate/ethanol. The filtrate and the washings were distilled under a reduced pressure to remove the solvent. Thus 0.89 g of the title compound was obtained as a pale-yellow crystal.

molecular formula; C₁₈ H₁₇ N₃ O₄ yield(%); 89 m.p. (°C.); 216-218 Mass; 340 (M+H)⁺ NMR δ (CDCl₃); 3.91 (3H, s), 4.15 (1H, brs), 4.68 (2H, brs), 4.77 (2H, d, J=5.6 Hz), 5.95 (2H, s), 6.79 (1H, d, 7.6 Hz), 6.85 (1H, brs), 6.88 (1H, dd, J=7.6 Hz, 1.6 Hz), 6.92 (1H, d, J=1.6 Hz), 7.21 (1H, d, J=2.8 Hz), 7.37 (1H, dd, J=9 Hz, 2.8 Hz), 7.72 (1H, d, J=9.2 Hz)

EXAMPLE 140 2-Hydroxy-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline ##STR201##

The title compound was prepared in a similar manner to that of Example 139.

molecular formula; C₁₇ H₁₅ N₃ O₄ yield(%); 16 m.p.(°C.); 215-217 (dec.) Mass; 326 (M+H)⁺ NMR δ (DMSO-d₆); 3.79 (3H, s), 4.62 (2H, d, J=5.6 Hz), 5.98 (2H, s), 6.84-6.87 (2H, m), 6.94 (1H, s), 7.09 (1H, d, J=8.8 Hz), 7.22 (1H, dd, J=8.8 Hz, 2.8 Hz), 7.60 (1H, d, J=2.8 Hz), 8.65 (1H, brt, J=5.6 Hz), 10.55 (1H, s)

EXAMPLE 141 2-Formyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline ##STR202##

A solution of 1.5 ml of dimethyl sulfoxide in 5 ml of methylene chloride was dropped into a solution of 1.0 ml (11 mmol) of oxalyl chloride in 10 ml of methylene chloride under stirring at -78° C. The obtained mixture was stirred at -78° C. for 15 minutes, followed by the dropwise addition of a solution of 0.74 g (2.2 mmol) of 2-hydroxymethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline in 7 ml of dimethyl sulfoxide. After the mixture thus obtained had been stirred at -78° C. for 20 minutes, 5 ml of triethylamine was dropped into the resulting mixture. The mixture thus prepared was stirred for 30 minutes, while raising the temperature to room temperature. Water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent. Thus, 0.74 g of the title compound was obtained as a crude brown oil.

molecular formula; C₁₈ H₁₅ N₃ O₄ yield(%); quantitative NMR δ (CDCl₃); 3.93 (3H, s), 4.86 (2H, d, J=5.6 Hz), 5.95 (2H, s), 6.28 (1H, brs), 6.78 (1H, d, J=8.0 Hz), 6.89 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.92 (1H, d, J=1.6 Hz), 7.09 (1H, d, J=2.8 Hz), 7.47 (1H, dd, J=9.2 Hz, 2.8 Hz), 7.97 (1H, d, J=9.2 Hz), 10.02 (1H, s)

EXAMPLE 142 2-Carboxy-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline ##STR203##

1.00 g of silver (I) oxide and 15 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 0.59 g (1.8 mmol) of the 2-formyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline prepared in Example 141 in 20 ml of 1,4-dioxane. The obtained mixture was stirred at 60° C. After 30 minutes, the reaction mixture was filtered through Celite and the filter cake was washed with a small amount of dioxane and water. The filtrate and washings were neutralized with 1N hydrochloric acid and extracted with chloroform/ethanol. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent. The crystal thus formed was recovered by filtration and washed with chloroform to give 0.34 g of the title compound as a pale-yellow crystal.

molecular formula; C₁₈ H₁₅ N₃ O₅ yield(%); 55 m.p.(°C.); 190-191 (dec.) Mass; 354 (M+H)⁺ NMR δ (DMSO-d₆); 3.90 (3H, s), 4.77 (2H, d, J=5.6 Hz), 5.97 (2H, s), 6.86 (1H, d, J=8.0 Hz), 6.92 (1H, d, J=8.0 Hz), 7.05 (1H, s), 7.49 (1H, dd, J=9.2 Hz, 2.8 Hz), 7.76 (1H, d, J=2.8 Hz), 7.79 (1H, d, J=9.2 Hz), 8.91 (1H, brt, J=5.6 Hz)

EXAMPLES 143 TO 145

The following compounds were prepared in a similar manner to that of Example 141 or 142.

EXAMPLE 143 4-(3-Formylbenzyl)amino-6,7,8-trimethoxyquinazoline ##STR204##

molecular formula; C₁₉ H₁₉ N₃ O₄ yield(%); quantitative m.p.(°C.); oily substance NMR δ (CDCl₃); 3.96 (3H, s), 4.04 (3H, s), 4.13 (3H, s), 4.97 (2H, d, J=5.6 Hz), 5.97 (1H, brt, J =5.6 Hz), 6.76 (1H, s), 7.53 (1H, t, J=7.6 Hz), 7.70 (1H, d, J=7.6 Hz), 7.81 (1H, d, J=7.6 Hz), 7.91 (1H, s), 8.64 (1H, s), 10.00 (1H, s)

EXAMPLE 144 4-(3-Carboxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR205##

molecular formula; C₁₉ H₁₉ N₃ O₅ yield(%); 45 m.p.(°C.); 245-246 (dec.) Mass; 370 (M+H)⁺ NMR δ (DMSO-d₆); 3.89 (3H, s), 3.93 (3H, s), 3.98 (3H, s), 4.86 (2H, d, J=5.6 Hz), 7.46 (1H, d, J=7.6 Hz), 7.56 (1H, s), 7.62 (1H, d, J=7.6 Hz), 7.83 (1H, d J=7.6 Hz), 7.95 (1H, s), 8.39 (1H, s), 8.83 (1H, brs)

EXAMPLE 145 4-(4-Acetylbenzyl)amino-6-methoxyquinazoline ##STR206##

molecular formula; C₁₈ H₁₇ N₃ O₂ yield(%); 41 m.p.(°C.); 204-206 Mass; 308 (M+H)⁺ NMR δ (CDCl₃); 2.60 (3H, s), 3.91 (3H, s), 4.97 (2H, d, J=5.6 Hz), 5.96 (1H, brs), 6.98 (1H, s), 7.42 (1H, d, J=9.2 Hz), 7.50 (2H, d, J=8.0 Hz), 7.82 (1H, d, J=9.2 Hz), 7.94 (2H, d, J=8.0 Hz), 8.61 (1H, s)

EXAMPLE 146 2-Hydroxyiminomethyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR207##

0.60 g of hydroxylamine hydrochloride and 3.0 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 1.00 g (2.93 mmol) of 2-formyl4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 30 ml of ethanol. The obtained mixture was stirred at 60° C. for 30 minutes and cooled by allowing to stand. The crystal thus precipitated was recovered by filtration, washed with ethanol and n-hexane and air-dried to give 1.00 g of the title compound as a white crystal.

molecular formula; C₁₇ H₁₃ N₄ O₃ Cl yield(%); 96 m.p.(°C.); 245-246 (dec.) Mass; 357 (M+1) NMR δ (DMSO-d₆); 4.69 (2H, d, J=6.0 Hz), 5.96 (2H, s), 6.84 (1H, d, J=7.6 Hz), 6.91 (1H, d, J=7.6 Hz, 1.6 Hz), 7.05 (1H, d, J=1.6 Hz), 7.72 (1H, d, J=8.8 Hz), 7.78 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.96 (1H, s), 8.45 (1H, d, J=2.0 Hz), 8.91 (1H, brt, J=6.0 Hz), 11.83 (1H, s)

EXAMPLES 147 TO 149

The following compounds were prepared in a similar manner to that of Example 146.

EXAMPLE 147 2-Hydroxyiminomethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyqinazoline ##STR208##

molecular formula; C₁₈ H₁₆ N₄ O₄ yield(%); 46 m.p.(°C.); 229-230 (dec.) Mass; 353 (M+H)⁺ NMR δ (DMSO-d₆); 3.88 (3H, s), 4.72 (2H, d, J=5.6 Hz), 5.96 (2H, s), 6.85 (1H, d, J=8.0 Hz), 6.91 (1H, d, J=8.0 Hz), 7.05 (1H, s), 7.40 (1H, dd, J=9.2 Hz, 2.8 Hz), 7.66 (1H, d, J=9.2 Hz), 7.69 (1H, d, J=2.8 Hz), 7.94 (1H, s), 8.62 (1H, brt, J=5.6 Hz), 11.63 (1H, s)

EXAMPLE 148 4-(3-Hydroxyiminomethylbenzyl)amino-6,7,8-trimethoxyquinazoline ##STR209##

molecular formula; C₁₉ H₂₀ N₄ O₄ yield(%); 56 m.p.(°C.); 231-232 (dec.) Mass; 369 (M+H)⁺ NMR δ (DMSO-d₆); 3.88 (3H, s), 3.91 (3H, s), 3.98 (3H, s), 4.80 (2H, d, J=6.0 Hz), 7.3-7.5 (3H, m), 7.52 (1H, s), 7.60 (1H, s), 8.11 (1H, s), 8.35 (1H, s), 8.60 (1H, brs), 11.17 (1H, s)

EXAMPLE 149 4-[4-(1-Hydroxyiminoethyl)benzyl]amino-6-methoxyquinazoline ##STR210##

molecular formula; C₁₈ H₁₈ N₄ O₂ yield(%); quantitative m.p.(°C.); 245-246 (dec.) Mass; 323 (M+H)⁺ NMR δ (DMSO-d₆); 2.13 (3H, s), 3.95 (3H, s), 4.97 (2H, d, J=5.6 Hz), 7.44 (2H, d, J=8.4 Hz), 7.63 (2H, d, J=8.4 Hz), 7.68 (1H, dd, J=9.2 Hz, 2.8 Hz), 7.83 (1H, d, J=9.2 Hz), 8.14 (1H, d, J=2.8 Hz), 8.84 (1H, s), 10.75 (1H, brs), 11.18 (1H, s)

EXAMPLE 150 2-Ethoxycarbonylmethoxyiminomethyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR211##

0.10 g (2.5 mmol) of sodium hydride was added to a suspension of 0.50 g (1.4 mmol) of 2-hydroxyiminomethyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 25 ml of dimethylformamide. The obtained mixture was stirred. After 30 minutes, 25 ml (2.3 mmol) of ethyl bromoacetate was dropped into the mixture. The mixture thus obtained was stirred at room temperature for several hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reducer pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 0.52 g of the title compound as a pale-yellow crystal.

molecular formula; C₂₁ H₁₉ N₄ O₅ Cl yield (% ); 84 m.p. (°C.); 154-155 Mass; 448 (M+1) NMR δ (CDCl₃); 1.29 (3H, t, J=7.2 Hz), 4.23 (2H, q, J=7.2 Hz), 4.74 (2H, d, J=5.2 Hz), 4.88 (2H, s), 5.96 (2H, s), 6.03 (1H, brt, J=5.2 Hz), 6.78 (1H, d, J=7.6 Hz), 6.87 (1H, d, J=7.6 Hz, 1.6 Hz), 6.93 (1H, d, J=1.6 Hz), 7.65 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.70 (1H, d, J=2.0 Hz), 7.84 (1H, d, J=8.8 Hz), 8.25 (1H, s)

EXAMPLE 151 4-(3-Amino-4-chlorobenzyl)amino-6-chloroquinazoline ##STR212##

A mixture comprising 1.00 g (2.86 mmol) of 4-(4-chloro-3-nitrobenzyl)amino-6-chloroquinazoline, 0.85 g of powdered iron, 10 ml of acetic acid and 50 ml of ethanol was heated under reflux for several hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 0.91 g of the title compound as a pale-yellow crystal.

molecular formula; C₁₅ H₁₂ N₄ Cl₂ yield(%); quantitative m.p.(°C.); 226-229 (dec.) Mass; 319 (M+H)⁺ NMR δ (CDCl₃); 4.19 (2H, brs), 4.73 (2H, d, J=6.0 Hz), 6.71 (1H, dd, J=8.0 Hz, 2.0 Hz), 6.83 (1H, d, J=2.0 Hz), 7.18 (1H, d, J=8.0 Hz), 7.64 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.72 (1H, brs), 7.74 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=2.0 Hz), 8.60 (1H, s)

EXAMPLE 152 4-(4-Chloro-3-formamidobenzyl)amino-6-chloroquinazoline ##STR213##

0.90 g (2.82 mmol) of the 4-(3-amino-4-chlorobenzyl)amino-6-chloroquinazoline prepared in Example 151 was dissolved in 15 ml of formic acid, followed by the addition of 1 ml of acetic anhydride. The obtained mixture was stirred at room temperature for several hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate to give 0.64 g of the title compound as a pale yellow crystal.

molecular formula; C₁₆ H₁₂ N₄ OCl₂ yield(%); 65 m.p.(°C.); 229-230 Mass; 347 (M+H)⁺ NMR δ (DMSO-d₆); 4.74 (2H, d, J=5.6 Hz), 7.15 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.43 (1H, d, J=8.4 Hz), 7.72 (1H, d, J=8.8 Hz), 7.80 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.16 (1H, d, J=2.0 Hz), 8.32 (1H, d, J=2.0 Hz), 8.45 (1H, s), 8.46 (1H, s), 8.95 (1H, brs), 9.83 (1H, brs)

EXAMPLE 153 4-(3-Formamido-4-methoxybenzyl)amino-6-chloroquinazoline ##STR214##

1 g of powdered iron was added in portions to a mixture comprising 1 g of 4-(3-nitro-4-methoxybenzyl)amino-6-chloroguinazoline, 4 ml of acetic acid, 4 ml of water and 40 ml of ethanol, while heating the mixture under mild reflux. The obtained mixture was heated under reflux for 2 hours and filtered to remove insolubles. Concentrated hydrochloric acid was added in portions to the brown filtrate obtained above to give a yellow transparent solution. This solution was cooled with ice to precipitate crystals. The crystals were recovered by filtration and dried to give 1.1 g of 4-(3-amino-4-methoxybenzyl)amino-6-chloroquinazoline hydrochloride. This hydrochloride was dissolved in ethanol/water and the obtained solution was made alkaline by adding a 15% aqueous solution of sodium hydroxide in portions. Water was added to the resulting alkaline solution in portions to precipitate crystals. The crystals were recovered by filtration, washed with water and dried to give 770 mg of 4-(8-amino-4-methoxybenzyl)amine-6-chloroquinazoline (an aniline derivative). Separately, 1 ml of formic acid was dropped into 2 ml of acetic anhydride under cooling with ice and the obtained mixture was heated at 50° C. for 15 minutes and immediately cooled with ice, followed by the addition of the above aniline derivative as such (in a crystalline state). The obtained mixture was reacted at that temperature for one hour and at room temperature for one hour, followed by the addition of water. The crystals thus formed were recovered by filtration, washed with water and dried to give 180 mg of the title compound.

molecular formula; C₁₇ H₁₅ N₄ O₂ Cl (342.786) yield(%); 60 m.p.(°C.); 208-209 Mass; 343 (MH)⁺ NMR δ (DMSO-d₆); 3.82 (3H, s), 4.68 (2H, d, J=5.7 Hz), 6.98 (1H, d, J=8.2 Hz), 7.09 (1H, dd, J=2.0 Hz, 8.2 Hz), 7.71 (1H, d, J=9.0 Hz), 7.79 (1H, dd, J=2.4 Hz, 9.0 Hz), 8.23 (1H, d, J=2.0 Hz), 8.27 (1H, d, J=2.4 Hz), 8.47 (2H, s), 8.88 (1H, t, J=5.7 Hz), 9.62 (1H, brs)

EXAMPLE 154 4-(3-Methanesulfonylamino-4-chlorobenzyl)amino-6-chloroquinazoline ##STR215##

75 μl of methanesulfonyl chloride was added to a mixture comprising 100 mg of 4-(3-amino-4-chlorobenzyl)amino-6-chloroquinazoline and 3 ml of pyridine. The obtained mixture was stirred at room temperature for 1.5 hours. 20 ml of water was added in portions to the reaction mixture to precipitate crystals. The crystals were recovered by filtration, washed with water and dried to give 109 mg of the title compound.

molecular formula; C₁₆ H₁₄ N₄ O₂ SCl₂ (397.284) yield(%); 88 m.p.(°C.); 209-210 Mass; 397 (MH)⁺ NMR δ (DMSO-d₆); 3.01 (3H, s), 4.75 (2H, d, J=5.7 Hz), 7.23 (1H, dd, J=2.2 Hz, 8.2 Hz), 7.45 (1H, d, J=8.2 Hz), 7.46 (1H, d, J=2.2 Hz), 7.73 (1H, d, J=9.0 Hz), 7.81 (1H, dd, J=2.4 Hz, 9.0 Hz), 8.45 (1H, d, J=2.4 Hz), 8.47 (1H, s), 8.97 (1H, brt, J=5.7 Hz), 9.4 (1H, brs)

EXAMPLES 155 TO 161

The following compounds were prepared in a similar manner to those of Examples 151 to 154.

EXAMPLE 155 4-(3-Amino-4-hydroxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR216##

molecular formula; C₁₈ H₂₀ N₄ O₄ yield(%); quantitative m.p.(°C.); amorphous Mass; 357 (M+H)⁺ NMR δ (CDCl₃); 3.68 (1H, brs), 3.82 (1H, brs), 3.95 (3H, s), 4.02 (3H, s), 4.11 (3H, s), 4.68 (2H, d, J=4.4 Hz), 6.61 (1H, brs), 6.64 (1H, d, J=7.6 Hz), 6.77 (1H, d, J=7.6 Hz), 7.01 (1H, s), 8.50 (1H, brs), 8.60 (1H, s)

EXAMPLE 156 4-(3-Ethoxycarbonylamino-4-ethoxycarbonyloxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR217##

molecular formula; C₂₄ H₂₈ N₄ O₈ yield(%); 54 m.p.(°C.); 229-230 (dec.) Mass; 501 (M+H)⁺ NMR δ (CDCl₃); 1.31 (3H, t, J=7.2 Hz), 1.40 (3H, t, J=7.2 Hz), 3.95 (3H, s), 4.03 (3H, s), 4.11 (3H, s), 4.21 (2H, q, J=7.2 Hz), 4.85 (2H, q, J=7.2 Hz), 4.81 (1H, d, J=5.2 Hz), 5.80 (1H, brt, J=5.2 Hz), 6.74 (1H, s), 6.87 (1H, s), 7.13 (1H, d, J=8.0 Hz), 7.20 (1H, d, J=8.0 Hz), 8.18 (1H, brs), 8.64 (1H, s)

EXAMPLE 157 4-[Benzoxazol-2(3H)-on-5-ylmethyl]amino-6,7,8-trimethoxyquinazoline ##STR218##

molecular formula; C₁₉ H₁₈ N₄ O₅ yield(%); 62 m.p.(°C.); 232-233 (dec.) Mass; 383 (M+H)⁺ NMR δ (DMSO-d₆); 3.87 (3H, s), 3.90 (3H, s), 3.96 (3H, s), 4.78 (2H, d, J=5.6 Hz), 7.06 (1H, s), 7.07 (1H, d, J=8.0 Hz), 7.20 (1H, d, J =8.0 Hz), 7.50 (1H, s), 8.35 (1H, s), 8.58 (1H, brt, J=5.6 Hz), 11.48 (1H, brs)

EXAMPLE 158 4-(4-Hydroxy-3-methanesulfonylaminobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR219##

molecular formula; C₁₉ H₂₂ N₄ O₆ S yield(%); 56 m.p.(°C.); 215-216 (dec.) Mass; 435 (M+H)⁺ NMR δ (DMSO-d₆); 2.91 (3H, s), 3.86 (3H, s), 3.89 (3H, s), 3.96 (3H, s), 4.65 (2H, d, J=5.6 Hz), 6.83 (1H, d, J=8.0 Hz), 7.04 (1H, dd, J=8.0 Hz, 2.0 Hz), 7.22 (1H, d, J=2.0 Hz), 7.50 (1H, s), 8.34 (1H, s), 8.52 (1H, brt, J=5.6 Hz), 8.66 (1H, brs), 9.75 (1H, brs)

EXAMPLE 159 4-(3-Amino-4-chlorobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR220##

molecular formula; C₁₈ H₁₉ N₄ O₃ Cl yield(%); 86 m.p.(°C.); 181-182 (dec.) Mass; 375 (M+H)⁺ NMR δ (CDCl₃); 3.95 (3H, s), 4.03 (3H, s), 4.08 (2H, brs), 4.13 (3H, s), 4.75 (2H, d, J=5.6 Hz), 5.65 (1H, brs), 6.67 (1H, s), 6.72 (1H, dd, J=8.0 Hz, 2.0 Hz), 6.81 (1H, d, J=2.0 Hz), 7.23 (1H, d, J=8.0 Hz), 8.65 (1H, s)

EXAMPLE 160 4-(4-Chloro-3-formamidobenzyl)amino-6,7,8-trimethoxyquinazoline ##STR221##

molecular formula; C₁₉ H₁₉ N₄ O₄ Cl yield(%); 68 m.p.(°C.); 202-204 (dec.) Mass; 403 (M+H)⁺ NMR δ (DMSO-d₆); 3.88 (3H, s), 3.91 (3H, s), 3.98 (3H, s), 4.75 (2H, d, J=5.6 Hz), 7.14 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.42 (2H, d, J=8.4 Hz), 7.52 (1H, s), 8.15 (1H, d, J=2.0 Hz), 8.32 (1H, s), 8.35 (1H, s), 8.67 (1H, brs), 9.83 (1H, brs)

EXAMPLE 161 4-(3-Acetamido-4-chlorobenzyl)amino-6-chloroquinazoline ##STR222##

molecular formula; C₁₇ H₁₄ N₄ OCl₂ (361.232) yield(%); 77 m.p.(°C.); 267-268 Mass; 361 (MH)⁺ NMR δ (DMSO-d₆); 2.06 (3H, s), 4.74 (2H, d, J=5.7 Hz), 7.17 (1H, dd, J=2.0 Hz, 8.2 Hz), 7.42 (1H, d, J=8.2 Hz), 7.69 (1H, brs), 7.72 (1H, d, J=9.0 Hz), 7.81 (1H, dd, J=2.4 Hz, 9.0 Hz), 8.45 (1H, d, J=2.4 Hz), 8.46 (1H, s), 8.96 (1H, brt, J=5.7 Hz), 9.48 (1H, brs)

EXAMPLE 162 4-(3,4-Dihydroxybenzyl)amino-6,7,8-trimethoxyquinazoline hydrochloride ##STR223##

30 ml of a 1.0M solution of boron trichloride in methylene chloride was dropped into a solution of 2.00 g (5.41 mmol) of 4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline in 150 ml of chloroform under stirring at room temperature. The obtained mixture was stirred at room temperature for 2 days, followed by the addition of methanol and the obtained mixture was distilled under a reduced pressure to remove the solvent. This procedure was repeated thrice and the obtained residue was purified by silica gel column chromatography (chloroform/n-hexane). Hydrochloric acid/ethanol was added to the eluate and the obtained mixture was distilled under a reduced pressure to remove the solvent, followed by the addition of ethanol. The crystals thus formed were recovered by filtration. Thus, 0.59 g of the title compound was obtained as a colorless needle.

molecular formula; C₁₈ H₁₉ N₃ O₅.HCl yield(%); 28 m.p.(°C.); 204-205 (dec.) Mass; 358 (M+H)⁺ NMR δ (DMSO-d₆); 3.98 (3H, s), 3.99 (3H, s), 3.99 (3H, s), 4.78 (2H, d, J=5.6 Hz), 6.65-7.71 (2H, m), 6.79 (1H, s), 7.94 (1H, s), 8.71 (1H, s), 8.90 (2H, brs), 10.54 (1H, brs), 14.06 (1H, brs)

EXAMPLE 163 4-(3,4-Dihydroxybenzyl)amino-6-chloroquinazoline hydrochloride ##STR224##

40 ml of a 1.0M solution of boron trichloride in methylene chloride was dropped into a solution of 2.00 g (6.37 mmol) of 4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 150 ml of chloroform under stirring at room temperature. The obtained mixture was stirred at room temperature for 2 days, followed by the addition of methanol, and the obtained mixture was distilled under a reduced pressure to remove the solvent. This procedure was repeated twice. The crystals thus precipitated were washed with methanol and recrystallized from ethanol to give 1.53 g of the title compound as a yellow crystal.

molecular formula; C₁₅ H₁₂ N₃ O₂ Cl.HCl yield(%); 71 m.p.(°C.); 154-155 (dec.) Mass; 302 (M+H)⁺ NMR δ (DMSO-d₆); 4.74 (2H, d, J=5.6 Hz), 7.67 (1H, dd, J=8.0 Hz, 2.0 Hz), 6.70 (1H, d, J=8.0 Hz), 6.81 (1H, d, J=2.0 Hz), 7.87 (1H, d, J=8.8 Hz), 8.02 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.76 (1H, d, J=2.0 Hz), 8.85 (1H, s), 8.90 (2H, brs), 10.42 (1H, brs)

EXAMPLE 164 2-(2-Methoxyethoxy)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR225##

A mixture comprising 20 ml of ethylene glycol monomethyl ether and 70 mg of 55% sodium hydride was heated to 100° C., followed by the addition of a mixture comprising 500 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline and 5 ml of ethylene glycol monomethyl ether. The obtained mixture was heated under reflux for 2 hours and poured into 50 ml of water. The obtained mixture was extracted with 50 ml of ethyl acetate twice. The organic layers were together washed with 70 ml of an aqueous solution of sodium chloride twice, dried over magnesium sulfate and concentrated under a reduced pressure to give a crystalline residue. This residue was reprecipitated from ethyl acetate/n-hexane to give 420 mg of the title compound.

molecular formula; C₁₉ H₁₈ N₃ O₄ Cl yield(%); 75 m.p.(°C.); 138-139 Mass; 388 (M+1)⁺ NMR δ (CDCl₃); 3.43 (3H, s), 3.78-3.81 (2H, m), 4.57-4.61 (2H, m), 4.73 (2H, d, J=5.2 Hz), 5.72 (1H, br), 5.96 (2H, s), 6.79-6.87 (3H, m), 7.52-7.58 (3H, m)

EXAMPLES 165 TO 177

The following compounds were prepared in a similar manner to those of Examples 162 to 164.

EXAMPLE 165 2-Methoxy-4-(3,4-methylenediokybenzyl)amino-6-chloroquinazoline ##STR226##

molecular formula; C₁₇ H₁₄ N₃ O₃ Cl yield(%); 15 m.p. (°C.); 187-189 Mass; 344 (M+1)⁺ NMR δ (CDCl₃); 4.03 (3H, s), 4.50 (2H, d, J=5.6 Hz), 5.91 (1H, br), 5.96 (2H, s), 6.78 (1H, d, J=7.6 Hz), 6.81 (1H, dd, J=7.6 Hz, 1.6 Hz), 6.82 (1H, d, J=1.6 Hz), 7.58-7.60 (3H, m)

EXAMPLE 166 2-Methoxy-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR227##

molecular formula; C₁₈ H₁₄ N₄ O₃ (334) yield(%); 23 m.p.(°C.); 224 (dec.) Mass; 335 (M+1)⁺ NMR δ (DMSO-d₆); 3.87 (3H, s), 4.60 (2H, brs), 5.95 (2H, s), 6.84 (2H, s), 6.95 (1H, s), 7.55 (1H, d, J=8.8 Hz), 7.94 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.83 (1H, d, J=1.6 Hz), 9.18 (1H, br)

EXAMPLE 167 2,6,7,8-Tetramethoxy-4-(3,4-methylenedioxybenzyl)aminoquinazoline ##STR228##

molecular formula; C₂₀ H₂₁ N₃ O₆ yield(%); 28 m.p.(°C.); 128-129 Mass; 400 (M+H)⁺ NMR δ (CDCl₃); 3.91 (3H, s), 4.04 (3H, s), 4.07 (3H, s), 4.14 (3H, s), 4.75 (2H, d, J=5.2 Hz), 5.51 (1H, brs), 5.97 (2H, s), 6.60 (1H, s), 6.80 (1H, d, J=8.0 Hz), 6.87 (1H, dd, J=8.0 Hz, 2.0 Hz), 6.90 (1H, d, J=2.0 Hz)

EXAMPLE 168 2-(2-Hydroxyethoxy)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR229##

molecular formula; C₁₈ H₁₆ N₃ O₄ Cl (373.5) yield(%); 97 m.p.(°C.); 191-193 Mass; 374 (M+1)⁺ NMR δ (DMSO-d₆); 3.65-3.69 (2H, m), 4.27 (2H, dd, J=8.8 Hz, 5.6 Hz), 4.60 (2H, d, J=5.2 Hz), 4.82 (1H, t, J=5.6 Hz), 5.95 (2H, s), 6.81-6.84 (2H, m), 6.92 (1H, s), 7.47 (1H, d, J=8.8 Hz), 7.65 (1H, dd, J=8.8 Hz, 2.2 Hz), 8.34 (1H, d, J=2.2 Hz), 8.82 (1H, br)

EXAMPLE 169 2-(2-Hydroxyethoxy)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR230##

molecular formula; C₁₉ H₁₆ N₄ O₄ (364) yield(%); 94 m.p.(°C.); 227-229 Mass; 365 (M+1)⁺ NMR δ (DMSO-d₆); 3.68 (2H, t, J=5.2 Hz), 4.30 (2H, t, J=5.2 Hz), 4.44 (1H, brs), 5.97 (2H, s), 6.82 (2H, s), 6.95 (1H, s), 7.54 (1H, d, J=8.4 Hz), 7.95 (1H, dd, J=8.4 Hz, 1.6 Hz), 8.78 (1H, d, J=1.6 Hz), 9.04 (1H, br)

EXAMPLE 170 2-(2-Methoxyethoxy)-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline ##STR231##

molecular formula; C₂₀ H₂₁ N₃ O₅ (383) yield(%); 68 m.p.(°C.); 118-119 Mass; 384 (M+1)⁺ NMR δ (DMSO-d₆); 3.26 (3H, s), 3.60 (2H, t, J=4.8 Hz), 3.61 (3H, s), 4.33 (2H, t, J=4.8 Hz), 4.63 (2H, d, J=6.0 Hz), 5.95 (2H, s), 6.81 (1H, d, J=7.6 Hz), 6.84 (1H, dd, J=7.6 Hz, 0.4 Hz), 6.91 (1H, d, J=0.4 Hz), 7.29 (1H, dd, J=8.8 Hz, 2.8 Hz), 7.40 (1H, d, J=8.8 Hz), 7.63 (1H, d, J=2.8 Hz), 8.62 (1H, br)

EXAMPLE 171 2-(2-Methoxyethoxy)-4-(benzimidazol-5-yl)methylamino-6-cyanoquinazoline ##STR232##

molecular formula; C₂₀ H₁₈ N₆ O₂ (374) yield (%); 68 m.p.(°C.); 267 (dec.) Mass; 375 (M+1)⁺ NMR δ (DMSO-d₆); 3.21 (3H, s), 3.60 (2H, s), 4.40 (2H, s), 4.82 (2H, s), 7.17-7.66 (4H, m), 7.94 (1H, d, J=9.6 Hz), 8.16 (1H, s), 8.81 (1H, s), 9.15 (1H, br)

EXAMPLE 172 2-Propoxy-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR233##

molecular formula; C₂₂ H₂₅ N₃ O₆ yield(%); 6 m.p.(°C.); 122-123 Mass; 428 (M+H)⁺ NMR δ (CDCl₃); 1.05 (3H, t, J=7.4 Hz), 1.89 (2H, m), 3.90 (3H, s), 4.03 (3H, s), 4.13 (3H, s), 4.41 (2H, t, J=7.0 Hz), 4.76 (2H, d, J=5.2 Hz), 5.49 (1H, brs), 5.97 (2H, s), 6.60 (1H, s), 6.80 (1H, d, J=8.0 Hz), 6.87 (1H, d, J=8.0 Hz), 6.90 (1H, s)

EXAMPLE 173 2-(3-Hydroxypropoxy)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR234##

molecular formula; C₁₉ H₁₈ N₃ O₄ Cl (387.5) yield(%); 60 m.p.(°C.); 118-120 Mass; 388 (M+1)⁺ NMR δ (CDCl₃); 2.02 (2H, J=5.6 Hz, 5.6 Hz), 3.70 (2H, t, J=5.6 Hz), 3.95 (1H, br), 4.66 (2H, t, J=5.6 Hz), 4.71 (2H, d, J=5.2 Hz), 5.95 (2H, s), 6.08 (1H, br), 6.77 (1H, d, J=8.0 Hz), 6.83 (1H, d, J=8.0 Hz), 6.85 (1H, s), 7.51 (1H, d, J=8.8 Hz), 7.56 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.61 (1H, d, J=2.0 Hz)

EXAMPLE 174 2-(4-Hydroxybutoxy)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR235##

molecular formula; C₂₀ H₂₀ N₃ O₄ Cl (401.5) yield(%); 23 m.p.(°C.); 121-124 Mass; 402 (M+1)⁺ NMR δ (CDCl₃); 1.47-1.73 (4H, m), 3.40-3.47 (2H, m), 4.20 (2H, t, J=6.7 Hz), 4.55 (2H, d, J=5.2 Hz), 5.72 (2H, s), 6.56 (1H, d, J=8.0 Hz), 6.66 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.71 (1H, d, J=1.6 Hz), 7.30 (2H, s), 7.88 (1H, brt, J=5.2 Hz), 7.99 (1H, s)

EXAMPLE 175 2-(4-Methoxybutoxy)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR236##

molecular formula; C₂₁ H₂₂ N₃ O₄ Cl (415.5) yield(%); 26 m.p.(°C.); 120-128 Mass; 416 (M+1)⁺ NMR δ (CDCl₃); 1.77 (2H, tt, J=8.8 Hz, 6.8 Hz), 1.90 (2H, tt, J=8.8 Hz, 6.8 Hz), 3.34 (3H, s), 3.44 (2H, t, J=6.8 Hz), 4.44 (2H, t, J=6.8 Hz), 4.72 (2H, d, J=5.2 Hz), 5.71 (1H, br), 5.96 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.84 (1H, dd, J=8.0 Hz, 1.8 Hz), 6.87 (1H, d, J=1.8 Hz), 7.53-7.59 (3H, m)

EXAMPLE 176 2-(6-Hydroxybenzyloxy)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR237##

molecular formula; C₂₂ H₂₄ N₃ O₄ Cl (429.5) yield(%); 66 m.p.(°C.); 144-146 Mass; 430 (M+1)⁺ NMR δ (CDCl₃); 1.14-1.40 (6H, m), 1.58-1.64 (2H, m), 3.06 (1H, br), 3.38 (2H, br), 4.17 (2H, t, J=6.8 Hz), 4.52 (2H, d, J=5.6 Hz), 5.73 (2H, s), 6.56 (1H, d, J=8.0 Hz), 6.66 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.71 (1H, d, J=1.6 Hz), 7.30 (2H, s), 7.85 (1H, br), 7.96 (1H, s)

EXAMPLE 177 2-Hydroxy-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR238##

molecular formula; C₁₆ H₁₂ N₃ O₃ Cl (329.5) m.p.(°C.); 257 (dec.) NMR δ (DMSO-d₆); 4.668 (2H, d, J=5.6 Hz), 5.967 (2H, s), 6.846-6.905 (2H, m), 6.995 (1H, s), 7.821-7.859 (2H, m), 8.508 (1H, s), 10.103 (1H, br), 11.916 (1H, s)

EXAMPLE 178 2-(2,3-Dihydroxypropyl)oxy-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR239##

100 mg of sodium hydride was added to a mixture comprising 300 mg of 5-hydroxy-2-phenyl-1,3-dioxane and 5 ml of dimethylformamide. The obtained mixture was heated to 80° C. After the bubbling had been discontinued, 300 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline was added in a crystalline state. The obtained mixture was heated at 140° C. for 2 hours and cooled, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography using an ethyl acetate/benzene mixture to give 118 mg of 2-(2-phenyl-1,3-dioxan-5-yl)oxy-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. 100 mg of this compound was hydrolyzed with concentrated hydrochloric acid/ethanol by a conventional process to give 60 mg of the title compound through rearrangement.

molecular formula; C₁₉ H₁₈ ClN₃ O₅ yield(%); 73 m.p.(°C.); 106-107 Mass; 404 (MH⁺) NMR δ (DMSO-d₆); 3.42 (2H, t, J=5.7 Hz), 3.79 (1H, sextet, J=5 Hz), 4.17 (1H, dd, J=6.6 Hz, 11.0 Hz), 4.31 (1H, dd, J=4.2 Hz, 11.0 Hz), 4.63 (2H, d, J=5.7 Hz), 4.66 (1H, t, J=6.0 Hz), 4.94 (1H, d, J=5.3 Hz), 5.98 (2H, s), 6.85 (2H, s), 6.95 (1H, s), 7.49 (1H, d, J=9.0 Hz), 7.68 (1H, dd, J=2.4 Hz, 9.0 Hz), 8.37 (1H, d, J=2.4 Hz), 8.83 (1H, t, J=5.7 Hz)

EXAMPLE 179 2-(3-Carboxypropyl)oxy-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR240##

250 μl of dimethyl sulfoxide was slowly dropped into a mixture comprising 150 μl of oxalyl chloride and 15 ml of methylene chloride which had been preliminarily cooled in a dry ice/acetone bath. After 10 minutes, a solution of 500 mg of 2-(2-hydroxyethyl)oxy-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline in 1 ml of dimethyl sulfoxide was dropped into the mixture prepared above at the same temperature and after 10 minutes, 1.4 ml of N,N-diisopropylethylamine was dropped thereinto at the same temperature. The obtained mixture was stirred at the same temperature for 10 minutes and brought to room temperature. After 20 minutes, 600 mg of ethoxycarbonylmethylenetriphenylphosphorane was added in a crystalline state to the resulting mixture to conduct a reaction for 30 minutes, followed by the addition of water. The obtained mixture was extracted with ethyl acetate and the extract was purified by silica gel column chromatography using an ethyl acetate/benzene mixture to give 400 mg of 2-(3-ethoxycarbonyl-2-propenyl)oxy-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline (cis/trans mixture).

The whole of the above compound was dissolved in 30 ml of ethyl acetate and catalytically reduced with a 10% palladium/carbon catalyst under normal pressure. The reaction mixture was purified by silica gel column chromatography using an ethyl acetate/benzene mixture to give 250 mg of 2-(3-ethoxycarbonylpropyl)oxy-4(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline (a saturated ester).

250 mg of the above saturated ester was dissolved in 50 ml of ethanol, followed by the addition of 1.7 ml of a 1N aqueous solution of sodium hydroxide. The obtained mixture was reacted at room temperature for 10 hours and then at 40° C. for 2 hours, cooled and neutralized by the addition of 1.7 ml of 1N aqueous hydrochloric acid, followed by the addition of water. The crystals thus formed were recovered by filtration and recrystallized from ethanol/water to give 200 mg of the title compound.

molecular formula; C₂₁ H₁₈ N₄ O₅ (406.398) yield(%); 86 m.p.(°C.); >290 Mass; 407 (MH⁺) NMR δ (DMSO); 1.93 (2H, quintet, J=7 Hz), 2.35 (2H, t, J=7.3 Hz), 4.32 (2H, t, J=6.6 Hz), 4.64 (2H, d, J=5.7 Hz), 5.98 (2H, s), 6.87 (2H, s), 6.97 (1H, s), 7.56 (1H, d, J=8.8 Hz), 7.96 (1H, dd, J=1.8 Hz, 8.8 Hz), 8.80 (1H, d, J=1.8 Hz), 9.05 (1H, t, J=5.7 Hz)

EXAMPLE 180 2-Methylthio-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR241##

20 ml of N,N-dimethylformamide and 221 mg of sodium thiomethoxide were added to 1 g of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline. The obtained mixture was stirred at 110° C. for one hour, neutralized with 1N hydrochloric acid and stirred at room temperature for one hour, followed by the addition of water. The crystals thus precipitated were recovered by filtration to give 780 mg of the title compound.

molecular formula; C₁₇ H₁₄ ClN₃ O₂ S yield(%); 76 m.p.(°C.); 214-216 Mass m/e; 360 (M+1) NMR δ (CDCl₃); 2.66 (3H, s), 4.85 (2H, d, J=5.6 Hz), 5.93 (2H, s), 6.73 (1H, d, J=8.0 Hz), 6.89 (1H, d, J=8.0 Hz), 6.93 (1H, s), 7.64 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.16 (1H, d, J =8.8 Hz), 8.77 (1H, d, J=2.0 Hz)

EXAMPLE 181 2-Morpholino-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR242##

A mixture comprising 338 mg of 2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline, 435 mg of morpholine and 20 ml of isopropyl alcohol was heated under reflux for 3 hours, followed by the addition of 30 ml of water under heating. The precipitate thus formed was recovered by filtration and washed with 30 ml of water and 30 ml of ethyl acetate. Thus, 310 mg of the title compound was obtained.

molecular formula; C₂₁ H₁₉ N₅ O₃ (389) yield(%); 80 m.p.(°C.); 270-272 (dec.) Mass; 390 (M+1)⁺ NMR δ (DMSO-d₆); 3.57-3.61 (4H, m), 3.73-3.79 (4H, m), 4.57 (2H, d, J=5.6 Hz), 5.95 (2H, s), 6.82 (1H, d, J=8.0 Hz), 6.85 (1H, d, J=8.0 Hz), 6.93 (1H, s), 7.27 (1H, d, J=8.8 Hz), 7.74 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.56 (1H, d, J=1.6 Hz), 8.75 (1H, brt, J=5.6 Hz)

EXAMPLES 182 TO 183

The following compounds were prepared in a similar manner to that of Example 181.

EXAMPLE 182 2-Morpholino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR243##

molecular formula; C₂₀ H₁₉ N₄ O₃ Cl (398.850) yield(%); 96 m.p.(°C.); 208-209 Mass; 399 (MH)⁺ NMR δ (DMSO-d₆); 3.61 (4H, t, J=5 Hz), 3.72 (4H, t, J=5 Hz), 4.58 (2H, d, J=5.7 Hz), 5.97 (2H, s), 6.85 (2H, s), 6.95 (1H, s), 7.28 (1H, d, J=9.0 Hz), 7.51 (1H, dd, J=2.4 Hz, 9.0 Hz), 8.18 (1H, d, J=2.4 Hz), 8.60 (1H, t, J=5.7 Hz)

EXAMPLE 183 2-Morpholino-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazoline ##STR244##

molecular formula; C₂₁ H₂₀ N₅ O₂ Cl (407.5) yield(%); 51 m.p.(°C.); 222-223 Mass; 410 (M+1)⁺ NMR δ (DMSO-d₆); 3.56-3.61 (4H, m), 3.74-3.80 (4H, m), 3.80 (3H, s), 4.58 (2H, d, J=5.2 Hz), 7.27-7.32 (2H, m), 7.44 (1H, d, J=1.6 Hz), 7.75 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.55 (1H, d, J=1.6 Hz), 8.80 (1H, brt, J=5.2 Hz)

EXAMPLE 184 2-(4-Hydroxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR245##

A mixture comprising 339 mg of 2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline, 500 mg of 4-hydroxypiperidine and 20 ml of N,N-dimethylformamide was heated under reflux for 5 hours and poured into 50 ml of water, followed by the addition of 50 ml of ethyl acetate. The obtained mixture was filtered to remove insolubles. The organic layer of the filtrate was dried over magnesium sulfate and concentrated under a reduced pressure to give a crystalline residue. This residue was washed with chloroform to give 145 mg of the title compound.

molecular formula; C₂₂ H₂₁ N₅ O₃ (403) yield(%); 36 m.p.(°C.); 229 Mass; 404 (M+1)⁺ NMR δ (DMSO-d₆); 1.19-1.30 (2H, m), 1.64-1.77 (2H, m), 3.21-3.30 (2H, m), 3.63-3.75 (1H, m), 4.34-4.38 (2H, m), 4.55 (2H, d, J=5.6 Hz), 4.66 (1H, d, J=4.0 Hz), 5.94 (2H, s), 6.80-6.86 (2H, m), 6.93 (1H, d, J=0.8 Hz), 7.24 (1H, d, J=8.4 Hz), 7.70 (1H, dd, J=8.4 Hz, 1.6 Hz), 8.52 (1H, d, J=1.6 Hz), 8.70 (1H, br)

EXAMPLES 185 TO 191

The following compounds were prepared in a similar manner to that of Example 184.

EXAMPLE 185 2-(4-Hydroxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR246##

molecular formula; C₂₁ H₂₁ N₄ O₃ Cl (412.877) yield(%); 56 m.p.(°C.); 157-158 Mass; 413 (MH⁺) NMR δ (DMSO-d₆); 1.2-1.3 (2H, m), 1.6-1.8 (2H, m), 3.1-3.2 (2H, m), 3.6-3.7 (1H, m), 4.3-4.4 (2H, m), 4.55 (2H, d, J=5.7 Hz), 4.65 (1H, d, J=4.4 Hz), 5.96 (2H, s), 6.84 (2H, s), 6.95 (1H, s), 7.24 (1H, d, J=9.0 Hz), 7.47 (1H, dd, J=2.4 Hz, 9.0 Hz), 8.13 (1H, d, J=2.4 Hz), 8.53 (1H, t, J=5.7 Hz)

EXAMPLE 186 2-(4-Hydroxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline ##STR247##

molecular formula; C₂₂ H₂₂ N₅ O₂ Cl (423.5) yield (%); 80 m.p.(°C.); 207-208 Mass; 424 (M+1)⁺ NMR δ (DMSO-d₆); 1.18-1.30 (2H, m), 1.65-1.76 (2H, m), 3.21-3.33 (2H, m), 3.30 (3H, s), 3.64-3.72 (1H, m), 4.29-4.37 (2H, m), 4.57 (2H, d, J=5.6 Hz), 4.66 (1H, d, J=1.8 Hz), 7.07 (1H, d, J=8.4 Hz), 7.24 (1H, d, J=8.8 Hz), 7.29 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.43 (1H, d, J=2.0 Hz), 7.71 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.51 (1H, d, J=2.0 Hz), 8.74 (1H, brt, J=1.8 Hz)

EXAMPLE 187 2-(2-Hydroxyethyl)amino-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR248##

molecular formula; C₂₁ H₂₄ N₄ O₆ yield(%); 38 m.p.(°C.); amorphous Mass; 429 (M+H)⁺ NMR δ (CDCl₃); 3.60 (2H, m), 3.88 (3H, s & 1H, m), 3.99 (3H, s), 4.01 (3H, s), 4.67 (2H, d, J=5.6 Hz), 5.32 (1H, brs), 5.53 (1H, brs), 5.97 (2H, s), 6.55 (1H, s), 6.80 (1H, d, J=8.0 Hz), 6.85 (1H, d, J=8.0 Hz), 6.89 (1H, s)

EXAMPLE 188 2-(2-Hydroxyethyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR249##

molecular formula; C₁₈ H₁₇ N₄ O₃ Cl yield(%); 47 m.p.(°C.); 138-139 Mass m/e; 373 (M+1) NMR δ (CDCl₃ (+DMSO-d₆)); 3.60 (2H, m), 3.79 (2H, t, J=4.8 Hz), 4.65 (2H, d, J=5.2 Hz), 5.94 (2H, s), 6.76 (1H, d, J=8.0 Hz), 6.85 (1H, dd, J=8.0 Hz, 2.0 Hz), 6.90 (1H, d, J=2.0 Hz), 7.34 (1H, d, J=8.8 Hz), 7.44 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.02 (2H, brs)

EXAMPLE 189 2-[N-(2-Hydroxyethyl)-N-methylamino]-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR250##

molecular formula; C₁₉ H₁₉ N₄ O₃ Cl yield(%); 48 m.p.(°C.); 146-148 Mass m/e; 387 (M+1) NMR δ (CDCl₃ (+DMSO-d₆)); 3.27 (3H, s), 3.82 (2H, t, J=4.8 Hz), 3.89 (2H, t, J=4.8 Hz), 4.67 (2H, d, J=5.6 Hz), 5.95 (2H, s), 6.77 (1H, d, J=8.0 Hz), 6.86 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.90 (1H, d, J=1.6 Hz), 7.43 (2H, m), 7.76 (1H, brs)

EXAMPLE 190 2-(2-Hydroxymethylpyrrolidin-1-yl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR251##

molecular formula; C₂₁ H₂₁ N₄ O₃ Cl (412.877) yield(%); 70 m.p.(°C.); 182-183 Mass; 413 (MH⁺) NMR δ (DMSO-d₆); 1.8-2.0 (4H, br 2 peaks), 3.4-3.7 (3H, br 2 peaks), 4.1-4.2 (1H, brs), 4.58 (2H, d, J=5.8 Hz), 5.96 (2H, s), 6.84 (1H, d, J=8.0 Hz), 6.88 (1H, dd, J=1.3 Hz, 8.0 Hz), 6.96 (1H, d, J=1.3 Hz), 7.23 (1H, d, J=8.8 Hz), 7.47 (1H, dd, J=2.4 Hz, 8.8 Hz), 8.15 (1H, d, J=2.4 Hz), 8.4-8.6 (1H, brs)

EXAMPLE 191 2-Bis(2-hydroxyethyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR252##

molecular formula; C₂₀ H₂₁ N₄ O₄ Cl (416.865) yield(%); 56 m.p.(°C.); 167-168 Mass; 417 (MH⁺) NMR δ (DMSO-d₆); 3.5-3.7 (8H, br 2 peaks), 4.56 (2H, d, J=5.7 Hz), 5.96 (2H, s), 6.85 (2H, s), 6.93 (1H, s), 7.22 (1H, d, J =9.0 Hz), 7.47 (1H, dd, J=2.4 Hz, 9.0 Hz), 8.15 (1H, d, J=2.4 Hz), 8.55 (1H, brt, J=5.7 Hz)

EXAMPLE 192 2-(1-Imidazolyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR253##

103 mg of imidazole was added to a suspension of 66 mg of sodium hydride in 6 ml of dimethylformamide at 0° C. The obtained mixture was stirred for 10 minutes. 500 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was added to the resulting mixture at room temperature. The mixture thus prepared was stirred at 100° C. for 20 minutes, followed by the addition of water. The crystals precipitated were recovered by filtration and washed with water and ethanol/acetone successively to give 325 mg of the title compound.

molecular formula; C₁₉ H₁₄ N₅ O₂ Cl yield(%); 59 m.p.(°C.); 275-276 (dec.) Mass m/e; 380 (M+1) NMR δ (DMSO-d₆); 4.74 (2H, d, J=5.6 Hz), 5.96 (2H, s), 6.85 (1H, d, J=8.0 Hz), 6.95 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.03 (1H, d, J=8.8 Hz), 7.08 (1H, d, J=1.2 Hz), 7.68 (1H, d, J=8.8 Hz), 7.78 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.94 (1H, d, J=1.2 Hz), 8.47 (1H, d, J=2.4 Hz), 8.58 (1H, t, J=2.4 Hz), 9.28 (1H, t, J=5.6 Hz)

EXAMPLES 193 TO 197

The following compounds were prepared in a similar manner to that of Example 192.

EXAMPLE 193 2-(Imidazol-1-yl)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR254##

molecular formula; C₂₀ H₁₄ N₆ O₂ (370) yield(%); 81 m.p.(°C.); >290 Mass; 371 (M+1)⁺ NMR δ (DMSO-d₆); 4.74 (2H, d, J=6.0 Hz), 5.95 (2H, s), 6.86 (1H, d, J=8.0 Hz), 6.95 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.04 (1H, d, J=1.6 Hz), 7.09 (1H, d, J=1.6 Hz), 7.73 (1H, d, J=8.4 Hz), 7.95 (1H, d, J=1.6 Hz), 8.06 (1H, dd, J=8.4 Hz, 1.6 Hz), 8.61 (1H, d, J=1.6 Hz), 8.87 (1H, d, J=1.6 Hz), 9.47 (1H, brt, J=6.0 Hz)

EXAMPLE 194 2-Pentylamino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR255##

molecular formula; C₂₁ H₂₃ N₄ O₂ Cl yield(%); 97 m.p.(°C.); 194-195 Mass m/e; 399 (M+1) NMR δ (CDCl₃); 0.86 (3H, t, J=7.2 Hz), 1.29 (4H, m), 1.58 (2H, quintet, J=6.8 Hz), 3.47 (2H, q, J=6.8 Hz), 4.78 (2H, d, J=5.6 Hz), 5.87 (2H, s), 6.66 (1H, d, J=8.0 Hz), 6.89 (1H, d, J=8.0 Hz), 6.94 (1H, s), 7.26 (1H, d, J=8.8 Hz), 7.41 (1H, d, J=8.8 Hz), 7.90 (1H, t, J=5.6 Hz), 8.55 (1H, s), 9.53 (1H, brs)

EXAMPLE 195 2-(2-Aminoethyl)amino-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR256##

molecular formula; C₂₁ H₂₅ N₅ O₅ yield(%); 87 m.p.(°C.); amorphous Mass; 428 (M+H)⁺ NMR δ (CDCl₃); 1.44 (2H, s), 2.93 (2H, t, J=6.0 Hz), 3.57 (2H, brs), 3.88 (3H, s), 4.00 (3H, s), 4.07 (3H, s), 4.70 (2H, d, J=4.8 Hz), 5.16 (1H, brs), 5.51 (1H, brs), 5.96 (2H, s), 6.56 (1H, s), 6.80 (1H, d, J=8.0 Hz), 6.86 (1H, d, J=8.0 Hz), 6.90 (1H, s)

EXAMPLE 196 2-Hydrazino-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR257##

molecular formula; C₁₉ H₂₁ N₅ O₅ yield(%); 12 m.p.(°C.); oily substance Mass; 400 (M+H)⁺ NMR δ (CDCl₃); 3.88 (3H, s), 3.99 (3H, s), 4.05 (3H, s), 4.66 (2H, d, J=3.6 Hz), 5.92 (2H, s), 6.75 (1H, d, J=8.0 Hz), 6.83 (1H, d, J=8.0 Hz), 6.87 (1H, s), 7.04 (2H, brs)

EXAMPLE 197 2-(Carbamoylmethyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR258##

molecular formula; C₁₈ H₁₆ N₅ O₃ Cl yield(%); 63 m.p.(°C.); 259-260 (dec.) Mass m/e; 386 (M+1) NMR δ (DMSO-d₆); 4.02 (2H, d, J=4.8 Hz), 4.66 (2H, d, J=5.6 Hz), 5.97 (2H, s), 6.86 (1H, d, J=8.0 Hz), 6.91 (1H, d, J=8.0 Hz), 6.99 (1H, s), 7.19 (1H, s), 7.50 (1H, d, J=8.8 Hz), 7.61 (1H, s), 7.83 (1H, d, J=8.8 Hz), 8.09 (1H, brs), 8.49 (1H, brs), 10.03 (1H, brs)

EXAMPLE 198 2-(3,4-Methylenedioxybenzyl)amino-4,6,7,8-tetramethoxyquinazoline ##STR259##

1.00 g (3.51 mmol) of 2-chloro-4,6,7,8-tetramethoxyquinazoline, 0.60 g (3.97 mmol) of piperonylamine and 0.60 g of sodium carbonate were mixed with 30 ml of isopropyl alcohol. The obtained mixture was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 0.12 g of the title compound as an oily substance.

molecular formula; C₂₀ H₂₁ N₃ O₆ yield(%); 9 m.p.(°C.); oily substance NMR δ (CDCl₃); 3.91 (3H, s), 4.02 (3H, s), 4.04 (6H, s), 4.63 (2H, d, J=6.0 Hz), 5.30 (1H, brs), 5.93 (2H, s), 6.75 (1H, d, J=8.0 Hz), 6.86 (1H, dd, J =8.0 Hz, 1.6 Hz), 6.92 (1H, d, J=1.6 Hz), 7.06 (1H, s)

EXAMPLE 199 2-Chloro-4,6,7,8-tetramethoxyquinazoline ##STR260##

5.00 g (17.3 mmol) of 2,4-dichloro-6,7,8-trimethoxyquinazoline was suspended in 100 ml of methanol, followed by the gradual addition of 1.5 g of sodium hydride. The obtained mixture was heated under reflux. After several hours, the reaction mixture was concentrated under a reduced pressure, followed by the addition of water. The crystal thus precipitated was recovered by filtration, washed with water and air-dried to give 4.80 g of the title compound as a pale-pink crystal.

yield(%); 97 m.p.(°C.); 119-120 Mass; 285 (M+1)⁺ NMR δ (CDCl₃); 3.98 (3H, s), 4.06 (3H, s), 4.12 (3H, s), 4.19 (3H, s), 7.17 (1H, s)

EXAMPLE 200 2-Amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR261##

2.0 g of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline was heated to 120° C. in 50 ml of ethanolic ammonia put in a pressure vessel for 18 hours, cooled and concentrated under a reduced pressure. The obtained residue was introduced to a silica gel column and eluted with a chloroform/methanol (9:1) mixture to give 830 mg of the title compound.

molecular formula; C₁₆ H₁₃ N₄ O₂ Cl yield(%); 44 m.p.(°C.); 285 (dec.) Mass; 329 (M+1)⁺ NMR δ (CDCl₃); 4.67 (2H, d, J=5.6 Hz), 4.98 (2H, br), 5.74 (1H, br), 5.96 (2H, s), 6.78 (1H, d, J=7.6 Hz), 6.83 (1H, dd, J=7.6 Hz, 1.6 Hz), 6.86 (1H, d, J=1.6 Hz), 7.38 (1H, d, J=9.6 Hz), 7.46-7.49 (2H, m)

EXAMPLE 201 2-Amino-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR262##

The title compound was prepared in a similar manner to those of Examples 199 and 200.

molecular formula; C₁₇ H₁₃ N₅ O₂ (319) yield(%); 60 m.p.(°C.); 284 (dec.) Mass; 320 (M+1)⁺ NMR δ (CDCl₃); 4.31 (2H, d, J=5.6 Hz), 5.25 (2H, brs), 5.58 (2H, s), 6.40 (1H, d, J=7.6 Hz), 6.51 (1H, dd, J=7.6 Hz, 1.2 Hz), 6.57 (1H, d, J=1.2 Hz), 6.95 (1H, d, J=8.4 Hz), 7.25 (1H, dd, J=8.4 Hz, 1.6 Hz), 8.00 (1H, br), 8.20 (1H, d, J=1.6 Hz)

EXAMPLE 202 2-(Methylcarbamoyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR263##

4 ml of dimethyl sulfoxide and 260 mg of methyl isocyanate were added to 500 mg of 2-amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was stirred at 50° C. for 3 hours and distilled under a reduced pressure to remove excess methyl isocyanate, followed by the addition of chloroform and water. The mixture thus obtained was filtered and the filtrate was extracted with chloroform twice. The organic layers were combined, washed with water twice, dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (benzene/acetone) and recrystallized (from benzene/chloroform/ethanol) to give 72 mg of the title compound.

molecular formula; C₁₈ H₁₆ N₅ O₃ Cl yield(%); 12 m.p.(°C.); 245-247 Mass m/e; 386 (M+1) NMR δ (DMSO-d₆); 2.75 (3H, d, J=4.4 Hz), 4.56 (2H, d, J=6.0 Hz), 5.95 (2H, s), 6.82 (1H, d, J=8.4 Hz), 6.92 (1H, d, J=8.4 Hz), 7.11 (1H, s), 7.56 (1H, d, J=8.8 Hz), 7.67 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.27 (1H, d, J=1.6 Hz), 8.90 (1H, t, J=6.0 Hz), 9.20 (1H, s), 9.38 (1H, d, J=4.4 Hz)

EXAMPLES 203 AND 204

The following compounds were prepared in a similar manner to that of Example 202.

EXAMPLE 203 2-Bis(methylcarbamoyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR264##

molecular formula; C₂₀ H₁₉ N₆ O₄ Cl yield(%); 8 amt. of product (mg); 45 m.p.(°C.); 243-245 Mass m/e; 443 (M+1) NMR δ (DMSO-d₆); 2.71 (6H, d, J=4.8 Hz), 4.53 (2H, d, J=6.0 Hz), 5.94 (2H, s), 6.80 (1H, d, J=8.0 Hz), 6.85 (1H, d, J=8.0 Hz), 6.95 (1H, s), 7.66 (1H, d, J=8.8 Hz), 7.72 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.32 (1H, dd, J=2.0 Hz), 8.85 (1H, dd, J=4.8 Hz), 9.01 (1H, t, J=6.0 Hz)

EXAMPLE 204 2-(n-Butylcarbamoyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR265##

molecular formula; C₂₁ H₂₂ N₅ O₃ Cl yield(%); 40 m.p.(°C.); 209-210 Mass m/e; 428 (M+1) NMR δ (DMSO-d₆); 0.89 (3H, t, J=7.2 Hz), 1.33 (2H, sextet, J=7.2 Hz), 1.45 (2H, quintet, J=7.2 Hz), 3.18 (2H, t, J=7.2 Hz), 4.56 (2H, d, J=6.0 Hz), 5.95 (2H, s), 6.83 (1H, d, J=8.0 Hz), 6.91 (1H, d, J=8.0 Hz), 7.09 (1H, s), 7.46 (1H, d, J=8.8 Hz), 7.66 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.27 (1H, d, J=2.0 Hz), 8.90 (1H, t, J=6.0 Hz), 9.17 (1H, s), 9.58 (1H, t, J=7.2 Hz)

EXAMPLE 205 2 -(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR266##

3.61 g of methyl isonipecotate, 2.32 g of triethylamine and 5 ml of 2-propanol were added to 1 g of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline prepared in Example 92. The obtained mixture was refluxed for 100 minutes. The mixture thus obtained was extracted with chloroform twice. The organic layers were combined, washed with water, dried over magnesium sulfate and freed from the solvent by distillation. The residue was recrystallized (from ethanol/water) to give 1.31 g of the title compound.

molecular formula; C₂₄ H₂₅ ClN₄ O₄ yield(%); 97 m.p.(°C.); 118-119 Mass; 469 (M+1) NMR δ (DMSO-d₆); 1.18 (3H, t, J=7.2 Hz), 1.42 (2H, m), 2.58 (1H, m), 2.98 (2H, m), 4.06 (2H, q, J=7.2 Hz), 4.56 (2H, m, J=5.6 Hz), 4.62 (2H, m), 5.96 (2H, s), 6.82 (1H, d, J=8.0 Hz), 6.86 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.94 (1H, d, J=1.6 Hz), 7.26 (1H, d, J=9.2 Hz), 7.48 (1H, dd, J=9.2 Hz, 2.4 Hz), 8.15 (1H, d, J=2.4 Hz), 8.56 (1H, brt, J=5.6 Hz)

EXAMPLE 206 2-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline hydrochloride ##STR267##

The title compound was prepared from the 2-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline prepared in Example 205 by the use of ethanol-hydrochloric acid-ethanol.

molecular formula; C₂₄ H₂₅ ClN₄ O₄.HCl yield(%); 97 m.p.(°C.); 174-175 NMR δ (DMSO-d₆): 1.20(3H, t, J=7.2 Hz), 1.59 (2H, m), 1.97 (2H, m), 2.75 (1H, m), 3.31 (2H, m), 4.0 9(2H, q, J=7.2 Hz), 4.53 (2H, m), 4.67 (2H, d, J=5.6 Hz), 5.98 (2H, s), 6.86 (1H, d, J=8.0 Hz), 6.90 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.01 (1H, d, J=1.6 Hz), 7.83 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.91 (1H, d, J=8.8 Hz), 8.52 (1H, d, J=2.0 Hz), 10.15 (1H, brs), 12.28 (1 H, brs)

EXAMPLE 207 2 -(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR268##

3.71 g of ethyl isonipecotate, 2.38 g of triethylamine and 10 ml of 2-propanol were added to 1 g of 2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was refluxed for 1 hour and cooled to room temperature. The crystals thus precipitated were recovered by filtration and washed with water and ether successively to give 1.126 g of the title compound.

molecular formula; C₂₅ H₂₅ N₅ O₄ yield(%); 83 m.p.(°C.); 192-193 Mass; 460 (M+1) NMR δ (CDCl₃); 1.26 (3H, t, J=7.2 Hz), 1.71 (2H, m), 1.99 (2H, m), 2.59 (1H, m), 3.12 (2H, brt, J=12.0 Hz), 4.15 (2H, q, J=7.2 Hz), 4.67 (2H, d, J=5.2 Hz), 4.82 (2H, dt, J=13.2 Hz, 3.6 Hz), 5.96 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.85 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.88 (1H, d, J=1.6 Hz), 7.42 (1H, brs), 7.61 (1H, dd, J=8.8 Hz, 1.6 Hz), 7.84 (1H, brs)

EXAMPLE 208 2-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline ##STR269##

3.5 g of ethyl isonipecotate, 2.25 g of triethylamine and 30 ml of 2-propanol were added to 1 g of 2-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was refluxed for 30 minutes and cooled to room temperature. The crystals thus precipitated were recovered by filtration and washed with water and ethanol successively to give 1.13 g of the title compound.

molecular formula; C₂₅ H₂₆ N₅ O₃ Cl yield(%); 85 m.p.(°C.); 202-203 Mass; 480 (M+1) NMR δ (CDCl₃); 1.26 (3H, t, J=7.2 Hz), 1.72 (2H, m), 1.99 (2H, m), 2.59 (1H, m), 3.13 (2H, brt, J=11.2 Hz), 3.90 (3H, s), 4.15 (2H, q, J=7.2 Hz), 4.69 (2H, d, J=5.6 Hz), 4.80 (2H, m), 6.91 (1H, d, J=8.4 Hz), 7.25 (1H, dd, J=8.4 Hz, 2.4 Hz), 7.42 (1H, d, J=2.4 Hz), 7.43 (1H, brs), 7.61 (1H, dd, J=8.8 Hz, 1.6 Hz), 7.87 (1H, brs)

EXAMPLE 209 2-[N-(3-Ethoxycarbonylpropyl)-N-methylamino]-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR270##

858 mg of ethyl N-methyl-4-aminobutyrate hydrochloride, 238 mg of triethylamine, 4 ml of 2-propanol and 2 ml of N,N-dimethylformamide were added to 400 mg of 2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was refluxed for 1 hour, cooled to room temperature and filtered. The filtrate was distilled under a reduced pressure to remove the solvent and the residue was recrystallized (from ethanol/water) to give 410 mg of the title compound.

molecular formula; C₂₄ H₂₅ N₅ O₄ yield(%); 78 m.p.(°C.); 152-153 Mass; 448 (M+1) NMR δ (CDCl₃); 1.22 (3H, t, J=6.8 Hz), 1.97 (2H, brs), 2.30 (2H, brs), 3.24 (3H, s), 3.75 (2H, brs), 4.10 (2H, q, J=6.8 Hz), 4.68 (2H, d, J=5.2 Hz), 5.96 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz), 6.87 (1H, s), 7.42 (1H, brs), 7.60 (1H, d, J=8.8 Hz), 7.81 (1H, brs)

EXAMPLES 210 TO 221

The following compounds were prepared in a similar manner to that of Examples 205 to 209.

EXAMPLE 210 2-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline hydrochloride ##STR271##

molecular formula; C₂₇ H₃₂ N₄ O₇.HCl yield(%); 65 m.p.(°C.); 148-150 Mass; 525 (M+1) NMR δ (CDCl₃); 1.275 (3H, t, J=7.2 Hz), 1.76 (2H, m), 2.03 (2H, m), 2.63 (1H, m), 3.38 (2H, m), 3.99 (3H, s), 4.08 (3H, s), 4.12 (3H, s), 4.17 (2H, q, J=7.2 Hz), 4.28 (2H, m), 4.63 (2H, d, J =6.0 Hz), 5.88 (2H, s), 6.68 (1H, d, J=8.0 Hz), 6.92 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.97 (1H, d, J=1.6 Hz), 8.23 (1H, s), 9.38 (1H, brs), 11.1 (1H, s)

EXAMPLE 211 2-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6,7,8-trimethoxyquinazoline hydrochloride ##STR272##

molecular formula; C₂₇ H₃₃ N₄ O₆ Cl.HCl yield(%); 93 m.p.(°C.); 177-178 Mass; 545 (M+1) NMR δ (CDCl₃); 1.27 (3H, t, J=7.2 Hz), 1.80 (2H, m), 2.06 (2H, m), 2.67 (1H, m), 3.40 (2H, m), 3.82 (3H, s), 3.98 (3H, s), 4.07 (3H, s), 4.11 (3H, s), 4.17 (2H, q, J=7.2 Hz), 4.27 (2H, m), 4.65 (2H, d, J=6.0 Hz), 6.84 (1H, d, J=8.8 Hz), 7.40 (1H, d, J=2.0 Hz), 7.48 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.23 (1H, s), 9.26 (1H, s), 11.27 (1H, brs)

EXAMPLE 212 2-(4-Ethoxycaxbonylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazoline hydrochloride ##STR273##

molecular formula; C₂₄ H₂₆ N₄ O₃ Cl₂.HCl yield(%); 97 m.p.(°C.); 201-204 Mass; 489 (M+1) NMR δ (DMSO-d₆); 1.17 (3H, t, J=7.2 Hz), 1.56 (2H, m), 1.93 (2H, m), 2.71 (1H, m), 3.30 (2H, m), 3.80 (3H, s), 4.06 (2H, q, J=7.2 Hz), 4.48 (2H, m), 4.66 (2H, d, J=5.2 Hz), 7.09 (1H, d, J=8.4 Hz), 7.34 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.49 (1H, d, J=2.0 Hz), 7.83 (2H, brs), 8.48 (1H, brs), 10.8 (1H, brs)

EXAMPLE 213 2-(Ethoxycarbonylmethyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR274##

molecular formula; C₂₀ H₁₉ N₄ O₄ Cl yield(%); 55 m.p.(°C.); 218-219 (dec.) Mass m/e; 415 (M+1) NMR δ (DMSO-d₆); 1.13 (3H, t, J=7.2 Hz), 4.07 (2H, q, J=7.2 Hz), 4.18 (2H, brs), 4.63 (2H, brd, J=4.0 Hz), 5.97 (2H, s), 6.85-6.92 (3H, m), 7.53 (1H, brs), 7.84 (1H, brd, J=8.0 Hz), 8.35 (1H, brs), 8.50 (2H, m)

EXAMPLE 214 2-(3-Ethoxycarbonylpropyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR275##

molecular formula; C₂₂ H₂₃ N₄ O₄ Cl yield(%); 44 m.p.(°C.); 96-98 Mass m/e; 443 (M+1) NMR δ (CDCl₃); 1.24 (3H, t, J=6.8 Hz), 1.96 (2H, quintent, J=7.2 Hz) 2.41 (2H, t, J=7.2 Hz) 3.54 (2H, q, J=7.2 Hz), 4.12 (2H, q, J=6.8 Hz), 4.68 (2H, q, J=5.2 Hz), 5.97 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz), 6.87 (1H, s), 7.30 (1H, d, J=8.0 Hz), 7.44 (1H, s), 7.47 (1H, d, J=8.0 Hz),

EXAMPLE 215 2-[N-(3-Ethoxycarbonylpropyl)-N-methylamino]-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline hydrochloride ##STR276##

molecular formula; C₂₃ H₂₅ N₄ O₄ Cl.HCl yield(%); 67 m.p.(°C.); 182-183 Mass; 457 (M+1) NMR δ (CDCl₃ +DMSO-d₆); 1.23 (3H, t, J=7.2 Hz), 1.90 (2H, brs), 2.25 (2H, brs), 2.84 (8H, brs), 3.56 (2H, brs), 4.10 (2H, q, J =7.2 Hz), 4.70 (2H, d, J=5.6 Hz), 5.94 (2H, s), 6.76 (1H, d, J=7.6 Hz), 6.87 (2H, m), 7.54 (1H, dd, J=9.2 Hz, 2.0 Hz), 8.40 (1H, d, J=2.0 Hz), 8.66 (1H, d, J=9.2Hz), 9.69 (1H, brs)

EXAMPLE 216 2-(5-Ethoxycarbonylpentyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR277##

molecular formula; C₂₄ H₂₇ N₄ O₄ Cl

yield (%); 46

m.p. (°C.); 109˜110

Mass m/e; 471 (M+1)

NMR δ (CDCl₃); 1.25 (3H, t, J=7.2 Hz), 1.43 (2H, quintet, J=7.6 Hz ), 1.66 (4H, m), 2.31 (2H, t, J=7.6 Hz), 3.49 (2H, q, J=7.6 Hz), 4.12 (2H, q, J=7.2 Hz), 4.68 (2H, d, J=5.2 Hz), 5.97 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz), 6.87 (1H, s), 7.43 (3H, m)

EXAMPLE 217 (S)-2- (N-2-Ethoxycarbonylpyrrolidin-1-yl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline hydrochloride ##STR278##

molecular formula; C₂₃ H₂₃ N₄ O₄ Cl.HCl

yield(%); 52

m.p.(°C.); 206˜208

Mass; 455 (M+1)

NMR δ (CDCl₃); 1.19 (3H, t, J=7.2 Hz), 2.17 (3H, m), 2.32 (1H, m), 4.12 (2H, m), 4.24 (2H, m), 4.62 (2H, m), 4.67 (1H, m), 5.93 (2H, s), 6.77 (1H, d, J=8.0 Hz), 6.86 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.89 (1H, d, J=1.6 Hz), 7.54 (1H, d, J=8.8 Hz), 8.38 (1H, s), 8.64 (1H, d, J=8.8 Hz), 9.67 (1H, brs), 13.38 (1H, brs)

EXAMPLE 218 2-(N-Ethoxycarbonylmethyl-N-methylamino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR279##

molecular formula; C₂₂ H₂₁ N₅ O₄

yield(%); 75

m.p.(°C.); 171˜172

Mass; 420 (M+1)

NMR δ (DMSO-d₆); 1.12 (3H, m), 3.18 (3H, s), 4.03 (2H, m), 4.38 (2H, m), 4.51 (2H, m), 5.95 (2H, s), 6.84 (3H, m), 7.30 (1H, m), 7.76 (1H, m), 8.58 (1H, s), 8.79 (1H, m)

EXAMPLE 219 2-[N-Ethyl-N-(3-ethoxycarbonylpropyl)amino]-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR280##

molecular formula; C₂₅ H₂₇ N₅ O₄ (461.522)

yield(%); 61

m.p.(°C.); 142˜143

Mass; 462 (M+1)

NMR δ (DMSO-d₆); 1.0˜1.15 (3H, br 2 peaks), 1.13 (3H, t, J=7.1 Hz), 1.65˜1.9 (2H, br 2 peaks), 2.15˜2.35 (2H, br 2 peaks), 3.58 (4H, brs), 4.01 (2H, q, J=7.1 Hz ), 4.58 (2H, d, J=5.7 Hz), 5.96 (2H, s), 6.84 (2H, s), 6.93 (1H, s), 7.25 (1H, brs), 7.72 (1H, dd, J1.8 Hz, 8.8 Hz), 8.56 (1H, d, J1.8 Hz), 8.72 (1H, t, J=5.7 Hz)

EXAMPLE 220 2-[N-(3-Ethoxycarbonylpropyl)-N-methylamino]-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline ##STR281##

molecular formula; C₂₄ H₂₆ N₅ O₃ Cl

yield(%); 72

m.p.(°C.); 127˜128

Mass; 468 (M+1)

NMR δ (DMSO-d₆); 1.11 (3H, t, J=7.2 Hz), 1.74 (2H, brs), 2.14 (2H, brs), 3.09 (3H, s), 3.62 (2H, brs), 3.81 (3H, s), 3.98 (2H, q, J=7.2 Hz), 4.61 (2H, d, J=6.0 Hz), 7.07 (1H, d, J=8.8 Hz), 7.20˜7.36 (2H, m), 7.42 (1H, s), 7.72 (1H, d, J=8.8 Hz), 8.55 (1H, s), 8.75 (1H, t, J=6.0 Hz)

EXAMPLE 221 (S)-2-(N-2-Ethoxycarbonylpyrrolidin-1-yl)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline hydrochloride ##STR282##

molecular formula; C₂₄ H₂₃ N₅ O₄.HCl

yield(%); 44

m.p.(°C.); 231˜232

Mass; 446 (M+1)

NMR δ (CDCl₃); 1.21 (3H, t, J=7.2 Hz), 2.19 (3H, m), 2.36 (1H, m), 4.15 (2H, m), 4.28 (2H, m), 4.62 (2H, m), 4.76 (1H, m), 5.95 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.86 (1H, d, J=8.0 Hz), 6.88 (1H, s), 7.80 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.82 (1H, d, J=1.6 Hz), 8.87 (1H, d, J=8.8 Hz), 9.85 (1H, brs), 13.81 (1H, s)

EXAMPLE 222 2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR283##

10 ml of ethanol, 5 ml of water and 820 mg of sodium hydroxide were added to 1 g of 2-(4-ethoxy-carbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was refluxed for 20 minutes, concentrated under a reduced pressure and neutralized with 1N hydrochloric acid. The crystals thus precipitated were recovered by filtration to give 920 mg of the title compound.

molecular formula; C₂₂ H₂₁ N₄ O₄ Cl

yield(%); 98

m.p. (°C.); 221˜222

Mass m/e; 441 (M+1)

NMR δ (DMSO-d₆); 1.38 (2H, m), 1.80 (2H, dd, J=13.2 Hz, 2.4 Hz), 2.48 (1H, m), 2.96 (2H, t, J=12.0 Hz), 4.54 (2H, d, J=5.6 Hz), 4.56 (2H, J=12.0 Hz, 3.2 Hz), 5.94 (2H, s), 6.81 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz), 6.93 (1H, s), 7.24 (1H, d, J=9.2 Hz), 7.46 (1H, dd, J=9.2 Hz, 2.0 Hz ), 8.13 (1H, d, J=2.0 Hz), 8.55 (1H, t, J=5.6 Hz)

EXAMPLE 223 Sodium 2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR284##

12 ml of a 1N aqueous solution of sodium hydroxide and 40 ml of water were added to 5.00 g (11.3 mmol) of the 2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline prepared in Example 222. The obtained mixture was dissolved by heating and cooled by allowing to stand. The crystals thus precipitated were recovered by filtration under suction, washed with a small amount of water, and vacuum-dried in the presence of phosphorus pentaoxide to give 4.34 g of the title compound.

molecular formula; C₂₂ H₂₀ ClN₄ O₄ Na

yield(%); 98

NMR δ (DMSO-d₄); 1.42(2H, m), 173(2H, m), 2.06(1H, m), 2.95(2H, m), 4.52(2H, m), 4.56(2H, d, J=5.6 Hz), 5.95(2H, s), 6.81(1H, d, J=8.0 Hz), 6.86(1H, dd, J=8.0 Hz, 1.6 Hz), 6.95(1H, d, J=1.6 Hz), 7.22(1H, d, J=9.2 Hz), 7.44(1H, dd, J=9.2 Hz, 2.4 Hz), 8.13(1H, d, J=2.4 Hz), 8.58(1H, brt, J=5.6 Hz)

EXAMPLE 224 Potassium 2-(4-Carboxypiperidino)-4-(3,4-methylene-dioxybenzyl)amino-6-chloroquinazoline ##STR285##

12.5 ml of a 1N aqueous solution of potassium hydroxide and 40 ml of water were added to 5.50 g (12.5 mmol) of the 2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzylamino)-6-chloroquinazoline prepared in Example 222. The obtained mixture was dissolved by heating and filtered. The filtrate was concentrated in a vacuum. Ethanol and ether were added to the obtained residue to precipitate crystals. The crystals were recovered by filtration, washed with ether, and vacuum-dried in the presence of phosphorus pentaoxide to give 4.69 g of the title compound.

molecular formula; C₂₂ H₂₀ ClN₄ O₄ K

yield (%); 78

m.p. (°C.); 230˜234 (dec.)

NMR δ (DMSO-d₆); 1.39(2H, m), 1.69(2H, m), 1.96(1H, m), 2.94(2H, m), 4.48(2H, m), 4.55(2H, d, J=5.6 Hz), 5.96(2H, s), 6.81(1H, d, J=8.0 Hz), 6.86(1H, dd, J=8.0 Hz, 1.6 Hz), 6.94(1H, d, J=1.6 Hz), 7.22(1H, d, J=8.8 Hz). 7.43(1H, dd, J=8.8 Hz, 2, 4 Hz), 8.11(1H, d, J=2.4 Hz), 8.50(1H, brt, J=5.6 Hz)

EXAMPLE 225 2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline hydrochloride ##STR286##

2.00 g (4.54 mmol) of the 2-(4-carboxy-piperidino)-4-(3,4-methylenedioxybenzylamino)-6-chloroquinazoline prepared in Example 222 was dissolved in a mixture comprising 25 ml of tetrahydrofuran and 25 ml of ethanol under heating, followed by the dropwise addition of 1.0 ml of an 8M ethanolic solution of hydrochloric acid. The obtained mixture was cooled by allowing to stand to precipitate crystals. The crystals were recovered by filtration, washed with tetrahydrofuran, and air-dried to give 1.87 g of the title compound.

molecular formula; C₂₂ H₂₁ N₄ O₄ Cl.HCl

yield(%); 86

m.p.(°C.); 284˜286

NMR δ (DMSO-d₆); 1.58(2H, m), 1.96(2H, m), 2.65(1H, m), 3.3(2H, m), 4.47(2H, m), 4.67(2H, d, J=5.6 Hz), 5.98(2H, s), 6.87(1H, d, J=8.0 Hz), 6.90(1H, dd, J=8.0 Hz, 1.6 Hz), 7.00(1H, d, J=1.6 Hz), 7.83(2H, brs), 8.49(1H, brs), 10.09(1H, hrs), 12.11(1H, brs), 12.40(1H, brs)

EXAMPLE 226 2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline methanesulfonate ##STR287##

2.00 g (4.54 mmol) of the 2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzylamino)-6-chloroquinazoline prepared in Example 222 was dissolved in a mixture comprising 25 ml of tetrahydrofuran and 25 ml of ethanol under heating, followed by the dropwise addition of 0.31 ml (4.78 mmol) of methanesulfonic acid. The obtained mixture was cooled by allowing to stand to precipitate crystals. The crystals were recovered by filtration, washed with tetrahydrofuran, and air-dried to give 2.21 g of the title compound.

molecular formula; C₂₂ H₂₁ N₄ O₄ Cl.CH₄ O₃ S

yield(%); 91

m.p. (°C.) ; 265˜266

NMR δ (DMSO-d₆); 1.59(2H, m), 1.97(2H, m), 2.32(3H, s), 2.65(1H, m), 3.3(2H, m), 4.40(2H, m), 4.68(2H, d, J=5.6 Hz), 5.98(2H, s), 6.87(1H, d, J=8.0 Hz). 6.90(1H, dd, J=8.0 Hz, 1.6 Hz), 6.98(1H, d, J=1.6 Hz), 7.67(1H, d, J=8.8 Hz), 7.84(1H, dd, J=8.0 Hz, 2.0 Hz), 8.42(1H, d, J=2.0 Hz), 9.95(1H, brs), 11.76(1H, brs), 12.37(1H, brs)

EXAMPLE 227 2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR288##

20 ml of ethanol and 2.0 ml of a 1N aqueous solution of sodium hydroxide were added to 318 mg of 2-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was stirred at 50° C. for 30 minutes and neutralized with 1N hydrochloric acid. The crystal thus precipitated was recovered by filtration and purified by silica gel column chromatography (chloroform/methanol) to give 116 mg of the title compound.

molecular formula; C₂₃ H₂₁ N₅ O₄

yield(%); 39

m.p.(°C.); 269˜271

Mass m/e; 432 (M+1)

NMR δ (DMSO-d₆); 1.40 (2H, m), 1.79 (2H, m), 2.41 (1H, m), 3.04 (1H, dr, J=11.2 Hz, 1.2 Hz), 4.55 (2H, d, J=5.6 Hz ), 4.57 (2H, m), 5.95 (2H, s), 6.82 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz ), 6.94 (1H, s), 7.25 (1H, d, J=8.8 Hz), 7.71 (1H, d, J=8.8 Hz ), 8.53 (1H, s), 8.72 (1H, t, J=5.6 Hz)

EXAMPLE 228 2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)-amino-6-cyanoquinazoline ##STR289##

30 ml of tetrahydrofuran, 80 ml of ethanol and 14 ml of a 1N aqueous solution of sodium hydroxide were added to 1.0 g of 2-(4-ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was stirred at room temperature for 16 hours and neutralized with 1N hydrochloric acid, followed by the addition of 100 ml of water. The crystals thus precipitated were recovered by filtration and recrystallized from tetrahydrofuran/ethanol/water to give 860 mg of the title compound.

molecular formula; C₂₃ H₂₂ N₅ O₃ Cl

yield(%); 91

m.p.(°C.); 277˜278 (dec.)

Mass m/e; 452 (M+1)

NMR δ (DMSO-d₆); 1.40 (2H, m), 1.84 (2H, m), 2.51 (1H, m), 3.05 (2H, dr, J=12 Hz, 2.4 Hz), 3.82 (3H, s), 4.59 (2H, d, J=5.6 Hz), 4.63 (2H, m), 7.08 (1H, d, J=8.4 Hz), 7.28 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.45 (1H, d, J=2.0 Hz), 7.74 (1H, dd, J=8.8 Hz, 2.0 Hz ), 8.54 (1H, d, J=2.0 Hz ), 8.79 (1H, t, J=5.6 Hz)

EXAMPLE 229 Sodium 2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline ##STR290##

1.00 g (2.21 mmol) of the 2-(4-carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline prepared in Example 228 was dissolved in a mixture comprising 30 ml of tetrahydrofuran and 40 ml of ethanol under heating, followed by the addition of 2.3 ml of a 1N aqueous solution of sodium hydroxide and 100 ml of water. The obtained mixture was concentrated in a vacuum to precipitate crystals. The crystals were recovered by filtration, washed with water, and air-dried to give 0.45 g of the title compound.

molecular formula; C₂₃ H₂₁ N₅ O₃ ClNa

yield(%); 43

NMR δ (DMSO-d₆); 1.45 (2H, m), 1.75 (2H, m), 2.12 (1H, m), 3.06 (2H, m), 3.81 (3H, s), 4.52 (2H, m), 4.58 (2H, d, J=5.6 Hz), 7.07 (1H, d, J=8.8 Hz), 7.24 (1H, d, J=8.4 Hz), 7.32 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.45 (1H, d, J=2.0 Hz), 7.69 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.54 (1H, d, J=2.0 Hz), 8.86 (1H, brt, J=5.6 Hz)

EXAMPLE 230 2-[N-(3-Carboxypropyl)-N-methylamino]-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR291##

20 ml of ethanol and 2.61 ml of a 1N aqueous solution of sodium hydroxide were added to 389 mg of 2-[N-(3-ethoxycarbonylpropyl)-N-methoxyamino]-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was stirred at room temperature for 4 hours and at 50° C. for 10 minutes and neutralized with 1N hydrochloric acid. The crystals precipitated were recovered by filtration, purified by silica gel column chromatography (chloroform/methanol) and recrystallized from ethanol/acetone/water to give 305 mg of the title compound.

molecular formula; C₂₂ H₂₁ N₅ O₄

yield(%); 84

m.p.(°C.); 138˜140

Mass m/e; 420 (M+1)

NMR δ (CDCl₃ (+DMSO-d₆)); 1.96 (2H, brs), 2.31 (brs), 3.24 (3H, s), 3.76 (2H, brs), 4.67 (2H, d, J=5.6 Hz), 5.94 (2H, s), 6.77 (1H, d, J=8.0 Hz), 6.86 (1H, d, J=8.0 Hz ), 6.91 (1H, s), 7.58 (1H, brs), 7.61 (1H, d, J=8.4 Hz), 8.48 (2H, m)

EXAMPLES 231 TO 245

The following compounds were prepared in a similar manner to those of Examples 222 to 230.

EXAMPLE 231 2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR292##

molecular formula; C₂₅ H₂₈ N₄ O₇

yield(%); 73

m.p.(°C.); 216˜217

Mass m/e; 297 (M+1)

NMR δ (CDCl₃); 1.80 (2H, m), 2.05 (2H, m), 2.65 (1H, m), 3.39 (2H, dt, J=10.8 Hz, 2.8 Hz), 3.98 (3H, s), 4.07 (3H, s), 4.13 (3H, s), 4.26 (2H, m), 4.70 (2H, d, J=6.0 Hz), 5.88 (2H, s), 6.69 (1H, d, J=7.6 Hz), 6.95 (1H, dd, J=7.6 Hz, 1.6 Hz), 7.02 (1H, d, J=1.6 Hz), 8.38 (1H, s), 9.36 (1H, s), 11.24 (1H, t, J=6.0 Hz)

EXAMPLE 232 2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6,7,8-trimethoxyquinazoline ##STR293##

molecular formula; C₂₅ H₂₉ N₄ O₆ Cl

yield(%); 90

m.p.(°C.); 197˜198

Mass m/e; 517 (M+1)

NMR δ (DMSO-d₆); 1.45 (2H, brs), 1.90 (2H, brs), 2.59 (1H, brs), 3.22 (2H, brs), 3.80 (3H, s), 3.90 (6H, s), 3.92 (3H, s), 4.39 (2H, brs), 4.65 (2H, d, J=5.2 Hz), 7.05 (1H, d, J=8.4 Hz), 7.33 (1H, d, J=8.4 Hz), 7.45 (1H, s), 7.76 (1H, brs), 10.70 (1H, brs)

EXAMPLE 233 2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline ##STR294##

molecular formula; C₂₃ H₂₄ N₄ O₅ (436)

yield(%); 79

m.p.(°C.); 263 (dec.)

Mass; 437 (M+1)⁺

NMR δ (DMSO-d₆); 1.51˜1.59 (2H, m), 1.86˜1.95 (2H, m), 2.59˜264 (1H, m), 3.21˜3.28 (2H, m), 4.39˜4.44 (2H, m), 4.67 (2H, d, J=5.6 Hz), 5.78 (2H, s), 6.85 (1H, d, J=7.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.99 (1H, s), 7.42 (1H, dd, J=9.2 Hz, 1.6 Hz), 7.72 (1H, d, J=9.2 Hz), 7.86 (1H, d, J=1.6 Hz), 10.02 (1H, br), 11.89 (1H, s)

EXAMPLE 234 2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-methoxyquinazoline ##STR295##

molecular formula: C₂₃ H₂₅ N₄ O₄ Cl (456.930)

yield (%): 81

m.p. (°C.); 245 (dec.)

Mass: 457 (MH⁺)

NMR; 1.3˜1.5 (2H, m), 1.79 (2H, d, J=10 Hz), 2.4˜2.5 (1H, m), 2.91 (2H, t, J=11 Hz), 3.81 (3H, s), 4.56 (2H, d, J=13 Hz), 4.60 (2H, d, J=5.7 Hz), 7.09 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=2.7 Hz, 9.2 Hz), 7.24 (1H, d, J=9.2 Hz), 7.32 (1H, dd, J=2.2 Hz, 8.6 Hz), 7.45 (1H, d, J=2.2 Hz), 7.49 (1H, d, J=2.7 Hz), 8.42 (1H, t, J=5.7 Hz), 12.15 (1H,

EXAMPLE 235 2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazoline ##STR296##

molecular formula; C₂₂ H₂₂ N₄ O₃ Cl₂

yield(%); 92

m.p.(°C.); 280˜281

Mass m/e; 461 (M+1)

NMR δ (DMSO-d₆); 1.59 (2H, m), 1.94 (2H, brd, J=11.6 Hz), 2.62 (1H, brs ), 3.32 (2H, m), 3.79 (3H, s), 4.52 (2H, d, J=13.6 Hz ), 4.64 (2H, d, J=4.8 Hz), 6.99 (1H, d, J=8.4 Hz), 7.30 (1H, d, J=8.4 Hz), 7.42 (1H, s), 7.69 (1H, d, J=8.8 Hz), 8.00 (1H, d, J=8.8 Hz), 8.51 (1H, s), 10.24 (1H, s), 12.42 (1H, s)

EXAMPLE 236 2-(4-Carboxypiperidino)-4-(benzimidazol-5-yl)methylamino-6-chloroquinazoline ##STR297##

molecular formula; C₂₂ H₂₁ N₆ O₂ Cl (436.903)

yield (%); 99

m.p.(°C.); 230 (dec.)

Mass; 437 (MH)⁺

NMR δ (DMSO-d₆); 1.3˜1.5 (2H, m), 1.82 (2H, d, J=10 Hz), 2.4˜2.5 (1H, m), 2.98 (2H, t, J=11 Hz), 4.60 (2H, d, J=13 Hz), 4.77 (2H, d, J=5.7 Hz), 7.2˜7.3 (2H, m), 7.45˜7.6 (3H, m), 8.16 (1H, s), 8.19 (1H, d, J=2.4 Hz), 8.68 (1H, t, J=5.7 Hz), 12.17 (1H, brs), 12.33 (1H, brs)

EXAMPLE 237 2-(Carboxymethyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR298##

molecular formula; C18H₁₅ N₄ O₄ Cl

yield(%); 64

m.p.(°C.); 260˜261 (dec.)

Mass m/e; 387 (M+1)

NMR δ (DMSO-d₆); 4.00 (2H, brs), 4.57 (2H, d, J=5.6 Hz), 5.93 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.86 (1H, d, J=8.0 Hz), 6.95 (1H, s), 7.35(1H, brs), 7.50 (1H, brs), 8.30˜8.50 (2H, m)

EXAMPLE 238 2-(3-Carboxypropyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR299##

molecular formula; C₂₀ H₁₉ N₄ O₄ Cl

yield(%); 88

m.p.(°C.); 170˜172

Mass m/e; 415 (M+1)

NMR δ (DMSO-d₆); 1.71 (2H, brs), 2.23 (2H, brs), 3.27 (2H, brs), 4.56 (2H, d, J=5.6 Hz), 5.95 (2H, s), 6.82 (3H, m), 6.95 (1H, s), 7.20 (1h, brs), 7.46 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.12 (1H, d, J=1.6 Hz)

EXAMPLE 239 2-(5-Carboxypentyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR300##

molecular formula; C₂₂ H₂₃ N₄ O₄ Cl

yield(%); 80

m.p.(°C.); 190˜192

Mass m/e; 443 (M+1)

NMR δ (DMSO-d₆); 1.25 (2H, brs), 1.47 (4H, brs), 2.16 (2H, brs), 3.31 (2H, brs), 4.60 (2H, brs), 5.94 (2H, s), 6.84 (2H, s), 6.96 (1H, s), 7.33 (1H, brs), 7.60 (1H, brs), 8.25 (1H, brs)

EXAMPLE 240 2-[N-(3-Carboxypropyl)-N-methylamino]-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR301##

molecular formula; C₂₁ H₂₁ N₄ O₄ Cl

yield(%); 92

m.p. (°C.); 148˜144

Mass m/e; 429 (M+1)

NMR δ (DMSO-d₆ (+CD₃ OD)); 1.79 (2H, brs), 2.20 (2H, brs), 3.21 (3H, s), 3.71 (2H, t, J=7.2 Hz), 4.65 (2H, s), 5.95 (2H, s), 6.81 (1H, d, J=8.0 Hz), 6.86 (1H, d, J=8.0 Hz), 6.95 (1H, s), 7.79 (1H, d, J=8.8 Hz), 7.85 (1H, d, J=8.8 Hz ), 8.49 (1H, s)

EXAMPLE 241 2-(N-Carboxymethyl-N-methylamino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR302##

molecular formula; C₂₀ H₁₇ N₅ O₄

yield(%); 68

m.p.(°C.); 268˜270

Mass m/e; 392 (M+1)

NMR δ (DMSO-d₆); 3.11 (3H, s), 4.13 (2H, brs), 4.56 (2H, m), 5.94 (2H, s), 6.83 (2H, m), 6.93 (1H, d, J=14.4 Hz), 7.20 (1H, m), 7.66 (1H, m), 8.51 (1H, s), 8.62 (1H, m)

EXAMPLE 242 2-[N-Ethyl-N-(3-carboxypropyl)amino]-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR303##

molecular formula; C₂₃ H₂₃ N₅ O₄ (433.468)

yield(%); 96

m.p.(°C.); 186˜187

Mass; 484 (M+1)

NMR δ (DMSO-d₆); 1.0˜1.15 (3H, br 2 peaks), 1.65˜1.85 (2H, br 2 peaks ), 2.1˜2.25 (2H, br 2 peaks), 3.57 (4H, brs), 4.58 (2H, d, J=5.7 Hz), 5.96 (2H, s), 6.84 (2H, s), 6.93 (1H, s), 7.26 (1H, d, J=8.8 Hz), 7.72 (1H, dd, J=1.8 Hz, 8.8 Hz), 8.56 (1H, d, J=1.8 Hz ), 8.71 (1H, brs)

EXAMPLE 243 2-[N-(3-Carboxypropyl)-N-methylamino]-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline ##STR304##

molecular formula; C₂₂ H₂₂ N₅ O₃ Cl

yield(%); 88

m.p.(°C.); 108˜109

Mass; 440 (M+1)

NMR δ (DMSO-d₆); 1.73 (2H, brs), 2.13 (2H, brs), 3.11 (3H, s), 3.63 (2H, brs), 3.82 (3H, s), 4.61 (2H, d, J=5.6 Hz), 7.07 (1H, d, J=8.4 Hz), 7.27 (1H, d J=8.8 Hz), 7.31 (1H, d, J=8.4 Hz), 7.43 (1H, s), 7.72 (1H, s), 8.55 (1H, s), 8.74 (1H, brt, J=5.6 Hz), 12.02 (1H, brs)

EXAMPLE 244 2-(4-Carboxypiperidino)-4-(benzimidazol-5-yl)methylamino-6-cyanoquinazoline ##STR305##

molecular formula; C₂₃ H₂₁ N₇ O₂ (427)

yield(%); 50

m.p.(°C.); >290

Mass; 428 (M⁺ +1)

NMR δ (DMSO-d₆); 1.29˜1.42 (2H, m), 1.76˜2.20 (2H, m), 2.39˜2.51 (2H, m), 2.99˜3.07 (3H, m), 4.60˜4.64 (2H, m), 4.76 (2H, d, J=5.6 Hz), 7.23 (1H, d, J=8.4 Hz), 7.25 (1H, d, J=8.8 Hz ), 7.51 (1H, d, J=8.4 Hz), 7.56 (1H, s), 7.71 (1H, dd, J=8.4 Hz, 1.6 Hz), 8.14 (1H, s), 8.57 (1H, d, J=1.6 Hz), 8.82 (1H, brt, J=5.6 Hz)

EXAMPLE 245 2- (4-Carboxypiperidino) -4-(3,4-methylenedioxybenzyl)amino-6-carbamoylquinazoline ##STR306##

molecular formula; C₂₃ H₂₃ N₅ O₅ (449)

yield(%); 6

m.p.(°C.); 180˜182 (dec.)

Mass; 450 (M+1)

NMR δ (DMSO-d₆); 1.39 (2H, m), 1.81 (2H, m), 2.48 (1H, m), 2.99 (2H, m), 4.55 (2H, d, J=5.6 Hz), 4.62 (2H, m), 5.93 (2H, s), 6.81 (1H, d, J=7.6 Hz), 6.85 (1H, dd, J=7.6 Hz, 1.6 Hz), 6.95 (1H, d, J=1.6 Hz), 7.20 (1H, d, J=8.8 Hz), 7.27 (1H, br), 7.71 (1H, br), 7.92 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.57 (1H, d, J=2.0 Hz), 8.59 (1H, brt, J=5.6 Hz), 12.09 (1H, br)

EXAMPLE 246 2-Benzyloxymethyl-4-chloro-6-methoxyquinazoline ##STR307##

30 ml of phosphorus oxychloride was added to a suspension of 1.50 g (5.06 mmol) of 2-benzyloxymethyl-6-methoxyquinazolin-4(3H)-one in 75 ml of acetonitrile. The obtained mixture was heated under reflux. After one hour, the reaction mixture was distilled under a reduced pressure to remove the solvent and the obtained residue was dissolved in chloroform. The obtained solution was washed with a saturated aqueous solution of sodium hydrogen-carbonate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 1.10 g of the title compound as a yellow crystal.

yield(%); 69

m.p.(°C.); 49˜50

Mass; 315 (M+1)⁺

NMR δ (CDCl₃); 3.98 (3H, s), 4.79 (2H, s), 4.84 (2H, s), 7.42 (1H, d, J=2.8 Hz), 7.26˜7.46 (5H, m), 7.57 (1H, dd, J=9.2 Hz, 2.8 Hz), 8.01 (1H, d, J=9.2 Hz)

EXAMPLE 247 2-Benzyloxymethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline ##STR308##

0.74 g (2.4 mmol) of the 2-benzyloxymethyl-4-chloro-6-methoxyquinazoline prepared in Example 246, 0.55 g (3.6 mmol) of piperonylamine and 0.50 g of sodium carbonate were mixed with 20 ml of isopropyl alcohol. The obtained mixture was heated under reflux. After 6 hours, the reaction mixture was distilled under a reduced pressure to remove the solvent and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from chloroform/n-hexane to give 1.01 g of the title compound as a yellow crystal.

molecular formula; C₂₅ H₂₃ N₃ O₄

yield(%); quantitative

m.p.(°C.); 158˜159

NMR δ (CDCl₃); 3.91 (3H, s), 4.69 (2H, s), 4.77 (2H, s), 4.79 (2H, d, J=5.6 Hz), 5.94 (2H, s), 6.77 (1H, d, J=7.6 Hz), 6.90 (1H, dd, J=7.6 Hz, 1.6 Hz ), 6.94 (1H, d, J=1.6 Hz), 7.10 (1H, brs ), 7.25˜7.35 (5H, m), 7.41˜7.44 (2H, m), 7.81 (1H, d, J=9.2 Hz)

EXAMPLE 248 2,6-Dichloro-4-(3,4-methylenedioxybenzyl)oxyquinazoline ##STR309##

molecular formula; C₁₆ H₁₀ Cl₂ N₂ O₃

yield(%); 55

m.p.(°C.); 141˜142

Mass m/e; 349 (M+1)

NMR δ (CDCl₃); 5.54(2H, s), 6.01(2H, s), 6.86(1H, d, J=8.8 Hz), 7.01(1H, d, J=8.8 Hz), 7.02(1H, s), 7.76(1H, dd, J=8.0 Hz, 2.4 Hz), 7.81(1H, dd, J=8.0 Hz, 0.8 Hz), 8.09(1H, dd, J=2.4 Hz, 0.8 Hz)

EXAMPLE 249 2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)oxy-6-chloroquinazoline ##STR310##

molecular formula; C₂₂ H₂₀ ClN₃ O₅

yield(%); 84

m.p.(°C.); 145˜147

Mass m/e; 442 (M+1)

NMR δ (DMSO-d₆); 1.47(2H, m), 1.88(2H, m), 2.49(1H, m), 3.10(2H, brt, J=13.2 Hz), 4.60(2H, brd, J=13.2 Hz), 5.43(2H, s), 6.01 (2H, s), 6.91(1H, d, J=8.0 Hz), 7.02(1H, d, J=8.0 Hz), 7.11 (1H, s), 7.39(1H, d, J=8.8 Hz), 7.61 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.77(1H, d, J=2.4 Hz)

EXAMPLE 250 2,6-Dichloro-4-(3,4-methylenedioxybenzyl)thioquinazoline ##STR311##

molecular formula; C₁₆ H₁₀ Cl₂ N₂ O₂ S

yield(%); 92

m.p.(°C.); 180˜182

Mass m/e; 365 (M+1)

NMR δ (CDCl₃); 4.55 (2H, s), 5.96 (2H, s), 6.77 (1H, d, J=8.4 Hz), 6.96 (1H, s), 6.96 (1H, d, J=8.4 Hz), 7.77 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.82 (1H, d, J=8.8 Hz ), 7.99 (1H, dd, J=2.0 Hz)

EXAMPLE 251 2-(4-Carboxypiperidino)-4- (3,4-methylenedioxybenzyl)thio-6-chloroquinazoline ##STR312##

molecular formula; C₂₂ H₂₀ ClN₃ O₄ S

yield(%); 98

m.p.(°C.); 153˜154

Mass m/e; 458 (M+1)

NMR δ (DMSO-d₆); 1.50(2H, m), 1.82(2H, m), 2.39(1H, brs), 3.18(2H, m), 4.48(2H, s), 4.55(2H, brs), 5.96(2H, s), 6.82(1H, d, J=8.0 Hz), 6.92(1H, d, J=8.0 Hz), 6.99(1H, s), 7.41 (1H, brd, J=8.8 Hz), 7.62(1H, brd, J=8.8 Hz), 7.69(1H, brs)

EXAMPLE 252 2-(4-Nitroxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR313##

molecular formula; C₂₁ H₂₀ ClN₅ O₅

yield(%); 11

m.p.(°C.); oily substance

Mass m/e; 458 (MH⁺)

NMR δ (CDCl₃); 1.71˜1.82(2H, m), 2.02˜2.10(2H, m), 3.56˜3.63(2H, m), 4.39˜4.44(2H, m), 4.66(2H, d, J=5.2 Hz), 5.18˜5.22(1H, m), 5.61(1H, brt, J=5.2 Hz), 5.96(2H, s), 6.79(1H, d, J=7.6 Hz), 6.84(1H, dd, J=7.6 Hz, 1.2 Hz), 6.87(1H, d, J=1.2 Hz), 7.39(1H, d, J=8.8 Hz), 7.43˜7.47(2H, m)

EXAMPLE 253 2,6-Dichloro-4- (3,4-methylenedioxybenzyl)aminoquinoline ##STR314## a) 2,4,6-Trichloroquinoline

The title compound was prepared from methyl 5-chloroanthranilate in a similar manner to that described in Journal of American Chemical Society, 68, 285 (1946).

NMR δ (CDCl₃); 7.55(1H,s), 7.74(1H, dd, J=9.0 Hz,2.2 Hz), 7.98(1H, d, J=9.0 Hz), 8.19(1H, d, J=2.2 Hz)

b) 2,6-Dichloro-4-(3,4-methylenedioxybenzyl)aminoquinoline

A reaction of a mixture comprising 500 mg of the compound prepared in the step (a), 350 mg of 3,4-methylenedioxybenzylamine, 1 ml of N,N-diisopropylethylamine and 4 ml of N-methyl-2-pyrrolidone was conducted on an oil bath of 130° C. for 10 hours. Water was added to the reaction mixture and the obtained mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to column chromatography with 5 to 20% ethyl acetate/hexane to give 430 mg of the title compound as a highly polar component.

molecular formula; C₁₇ H₁₂ Cl₂ N₂ O₃

m.p.(°C.); 198˜199

Mass m/e; 347 (M+1)

NMR δ (CDCl₃); 4.39(2H, d, J=4.9 Hz), 5.21(1H, t, J=4.9 Hz), 6.00(2H, s), 6.47(1H, s), 6.82˜6.87(3H, m), 7.58(1H, dd, J=9.0 Hz, 2.2 Hz), 7.65(1H, d, J=2.2 Hz), 7.84(1H, d, J=9.0 Hz)

Simultaneously, 190 mg of 4,6-dichloro-2- (3,4-methylenedioxybenzyl)aminoquinoline was obtained as a lowly polar component.

NMR δ (CDCl₃); 4.58(2H, d, J=5.7 Hz), 5.00(1H, brt, J=5.7 Hz), 5.94(2H, s), 6.74(1H, s), 6.77(1H, d, J=7.9 Hz), 6.84(1H, dd, J=7.9 Hz, 1.6 Hz), 6.88(1H, d, J=1.6 Hz), 7.50(1H, dd, J=9.0 Hz, 2.4 Hz), 7.62(1H, d, J=9.0 Hz), 7.96(1H, d, J=2.4 Hz)

EXAMPLE 254 2,6-Dichloro-4-(3-chloro-4-methoxybenzylamino)quinoline ##STR315##

The titled compound was prepared in a similar manner to that of Example 253.

molecular formula; C₁₇ H₁₃ Cl₃ N₂ O

yield(%); 59

m.p. (°C.); 204˜205

NMR δ (CDCl₃): 3.91(3H, s), 3.40(3H, s), 4.38(2H, d, J=5.1 Hz), 4.97(1H, t, J=5.1 Hz), 5.93(1H, s), 6.93(1H, d, J=8.4 Hz), 7.24(1H, dd, J=8.4 Hz, 2.2 Hz), 7.40(1H, d, J=2.2 Hz), 7.50(1H, dd, J=8.8 Hz, 2.2 Hz), 7.59(1H, d, J=2.2 Hz 7.71(1H, d, J=8.8 Hz)

EXAMPLE 255 2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinoline ##STR316## a) 2-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinoline

A reaction of a mixture comprising 130 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinoline, 500 μl of ethyl isonipecotate and 1 ml of N-methyl-2-pyrrolidone was conduct on an oil bath at 150° C. for 3 hours. The reaction mixture was cooled, followed by the addition of water. The resulting mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 20 to 50% ethyl acetate/hexane to give 150 mg of the title compound.

NMR δ (CDCl₃); 1.28(3H, t, J=7.1 Hz), 1.70˜1.81(2H, m), 1.95˜2.02(2H, m), 2.54(1H, tt, J=11.2 Hz, 3.8 Hz), 2.97˜3.06(2H, m), 4.14(2H, q, J=7.1 Hz), 4.32˜4.39(4H, m), 4.86(1H, t, J=5.5 Hz), 5.98(3H, s), 6.81(1H, d, J=7.7 Hz), 6.84˜6.89(2H, m), 7.39(1H, dd, J=9.0 Hz, 2.4 Hz), 7.47(1H, d, J=2.4 Hz), 7.55(1H, J=9.0 Hz)

b) 2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinoline

A reaction of a mixture comprising 150 mg of the compound prepared in the step (a), 1 ml of a 1N aqueous solution of sodium hydroxide and 10 ml of ethanol was conducted on an oil bath at 60° C. for 2 hours. The reaction mixture was concentrated, followed by the addition of water. The resulting mixture was neutralized by the addition of 1 ml of 1N hydrochloric acid to precipitate crystals. The crystals were recovered by filtration, washed with water, and dried to give 130 mg of the title compound.

molecular formula; C₂₃ H₂₂ ClN₃ O₄

yield(%); 92

m.p.(°C.); 235˜237

Mass m/e; 440 (M+1)

NMR δ (DMSO-d₆); 1.37˜1.50(2H, m), 1.77˜1.86(2H, m), 2.89˜3.00(2H, br, 3 peak). 4.20∞4.28(2H, br, 2 peak), 4.42(2H, d, J=5.7 Hz), 5.96(2H, s), 5.97(1H, s), 6.85(1H, d, J=7.9 Hz), 6.92(1H, dd, J=7.9 Hz, 1.5 Hz), 6.98(1H, d, J=1.5 Hz), 7.42(2H, brs), 7.58(1H, brs), 8.15(1H, brs)

EXAMPLE 256 2-(4-Carboxypiperidino)-4-(3- chloro-4-methoxybenzyl)amino-6-chloroquinoline ##STR317##

The title compound was prepared in a similar manner to that of Example 255.

molecular formula; C₂₃ H₂₃ Cl₂ N₃ O₃

m.p.(°C.); 282˜283

Mass m/e; 460 (M+1)

NMR δ (DMSO-d₆); 1.36˜1.48(2H, m), 1.76˜1.84(2H, m), 2.43˜2.53(1H, m), 2.91(2H, t, J=11.2 Hz), 4.26(2H, brd, J=13.2 Hz), 4.44(2H, d, J=5.9 Hz), 5.97(1H, s), 7.10(1H, d, J=8.6 Hz), 7.36(1H, dd, J=8.6 Hz, 2.2 Hz), 7.38(2H, s), 7.50(2H, brs and d, J=2.2 Hz), 8.11(1H, s)

EXAMPLE 257 2-Methoxy-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinoline ##STR318##

A mixture comprising 200 mg of 2,6-dichloro-4-(3-chloro-4-methoxybenzyl)aminoquinoline, 0.5 ml of methanol, 200 mg of potassium t-butoxide and 3 ml of 1,4-dioxane was heated under reflux for one hour and cooled, followed by the addition of water. The resulting mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 10 to 30% ethyl acetate/hexane and recrystallized from ethyl acetate/hexane to give 150 mg of the title compound.

molecular formula; C₁₈ H₁₆ Cl₂ N₂ O₂

yield(%); 76

m.p.(°C.); 170˜171

NMR δ (CDCl₃); 3.93(3H, s), 4.42(2H, d, J=5.2 Hz), 5.22(1H, t, J=5.2 Hz), 6.46(1H, s), 6.96(1H, d, J=8.4 Hz), 7.25(1H, dd, J=8.4Hz, 2.2 Hz), 7.41(1H, d, J=2.2 Hz), 7.59(1H, dd, J=9.0 Hz, 2.2 Hz), 7.66(1H, d, J=2.2 Hz), 7.85(1H, d, J=9.0 Hz)

EXAMPLE 258 2-(3,4-Methylenedioxybenzylamino)-4-(4-carboxypiperidino)-6-chloroquinoline ##STR319##

130 mg of the title compound was prepared from 140 mg of the 4,6-dichloro-2-(3,4-methylenedioxybenzyl)aminoquinoline prepared in the step (b) of Example 253 as a by-product in a similar manner to that of Example 255.

molecular formula; C₂₃ H₂₂ ClN₃ O₄

yield(%); 99

m.p.(°C.); 270˜272

Mass m/e; 440 (M+1)

NMR δ (DMSO-d₆); 1.78˜1.89(2H, m), 1.96˜2.04(2H, m), 2.70˜2.79(2H, m), 3.26˜3.36(2H, m), 4.49(2H, d, J=5.7 Hz), 5.96(2H, s), 6.37(1H, s), 6.85(2H, s), 6.94(1H, s), 7.37(1H, t, J=5.7 Hz), 7.41(1H, dd, J=8.8 Hz, 2.4 Hz), 7.46(1H, d, J=8.8 Hz), 7.60(1H, d, J=2.4 Hz)

EXAMPLE 259 2-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinoline ##STR320## a) 4-Hydroxyquinolin-2-one-6-carboxylic add

The title compound was prepared from dimethyl 4-aminobenzene-1,4-dicarboxylate in a similar manner to that described in Journal of American Chemical Society, 68, 1285 (1946).

NMR δ (DMSO-d.sub. 6); 5.79(1H, s), 7.31(1H, d, J=8.6 Hz), 8.02(1H, dd, J=8.6 Hz, 2.0 Hz), 8.39(1H, d, J=2.0 Hz), 11.51(1H, s), 11.63(1H, brs), 12.86(1H, brs)

b) 2,4-Dichloroquinoline-6-carboxamide

A mixture comprising 9 g of the compound prepared in the step (a) and 50 ml of phosphorus oxychloride was heated under reflux for one hour. The reaction mixture was concentrated and ethyl acetate/acetone was added to the obtained residue to form a homogeneous suspension. This suspension was gradually poured into concentrated aqueous ammonia cooled with ice under stirring. After 30 minutes, the crystals thus precipitated were recovered by filtration, washed with water and ethyl acetate, and dried to give 8.96 g of the title compound.

NMR δ (DMSO-d₆); 7.72(1H, brs), 8.06(1H, s), 8.10(1H, d, J=8.8 Hz), 8.34(1H, dd, J=8.8 Hz, 2.0 Hz), 8.43(1H, brs). 8.73(1H, d, J=2.0 Hz)

c) 2,4-Dichloro-6-cyanoquinoline

A mixture comprising 3 g of the compound prepared in the step (b), 300 mg of lithium chloride and 30 ml of phosphorus oxychloride was heated under reflux for 2 hours. The reaction mixture was concentrated, followed by the addition of 120 ml of benzene. The resulting mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. The benzene layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered through a silica gel bed. The silica gel was further washed with benzene. The benzene solutions were combined and concentrated and the residue was recrystallized from ethyl acetate/hexane to give 2.15 g of the title compound.

NMR δ (CDCl₃); 7.65(1H, s), 7.95(1H, dd, J=8.8 Hz, 1.8 Hz), 8.14(1H, d, J=8.8 Hz), 8.60(1H, d, J=1.8 Hz)

d) 2-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinoline

A reaction of a mixture comprising 1 g of the compound prepared in the step (c), 1 g of 3-chloro-4-methoxybenzylamine hydrochloride, 2.4 ml of N,N-diisopropylethylamine and 10 ml of N-methyl-2-pyrrolidone was conducted on an oil bath at 130° C. for one hour. The reaction mixture was cooled, followed by the addition of water and ethyl acetate. The crystals thus precipitated were recovered by filtration, washed with water and ethyl acetate, and dried to give 610 mg of the title compound.

molecular formula; C₁₈ H₁₃ Cl₂ N₃ O

yield(%); 38

m.p.(°C.); 254˜255

NMR δ (CDCl₃); 3.84(3H, s), 4.45(2H, d, J=4.9 Hz), 5.41(1H, d, J=4.9 Hz), 6.54(1H, s), 6.98(1H, d, J=8.4 Hz), 7.26(1H, dd, J=8.4 Hz, 2.2 Hz), 7.41(1H, d, J=2.2 Hz), 7.80(1H, dd, J=8.8 Hz, 1.6 Hz), 7.97(1H, d, J=8.8 Hz), 8.08(1H, d, J=1.6 Hz)

EXAMPLE 260 2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinoline ##STR321## a) 2-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzylamino)-6-cyanoquinoline

A mixture comprising 750 mg of 2-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinoline, 1.6 ml of isonipecotic acid and 5 ml of N-methyl-2-pyrrolidone was heated on an oil bath at 130° C. for 3 hours and cooled, followed by the addition of water. The resulting mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (20 to 40% ethyl acetate/hexane) and thereafter recrystallized from ethyl acetate/hexane to give 860 mg of the title compound.

NMR δ (CDCl₃); 1.26(3H, t, J=7.1 Hz), 1.68˜1.79(2H, m), 1.95˜2.03(2H, m). 2.58(1H, tt, J=11.0 Hz, 4.0 Hz), 3.03˜3.12(2H, m), 3.92(3H, s), 4.15(2H, q, J=7.1 Hz), 4.36˜4.43(4H, m), 5.08(1H, t, J=5.1 Hz), 5.94(1H, s), 6.95(1H, d, J=8.4 Hz), 7.26(1H, dd, J=8.4 Hz, 2.2 Hz), 7.42(1H, d, J=2.2 Hz), 7.55˜7.61(2H, m), 7.88(1H, s)

b) 2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzylamino)-6-cyanoquinoline

A mixture comprising 500 mg of the compound prepared in the step (a), 2 ml of a 1N aqueous solution of sodium hydroxide, 20 ml of tetrahydrofuran and 25 ml of ethanol was reacted at 50° C. for 2 hours, followed by the addition of 2 ml of 1N hydrochloric acid. About 20 ml of the solvents was distilled away to precipitate crystals. The crystals were recovered by filtration, washed with water and ethyl acetate, and dried to give 460 mg of the title compound.

molecular formula; C₂₄ H₂₃ ClN₄ O₃

yield(%); 98

m.p.(°C.); 274˜276 (dec.)

NMR δ (DMSO-d₆); 1.35˜1.47(2H, m), 1.78˜1.87(2H, m), 2.47˜2.56(1H, m), 2.95˜3.04(2H, m), 3.81(3H, s), 4.30˜4.39(2H, m), 4.46(2H, d, J=5.7 Hz), 6.01(1H, s), 7.11(1H, d, J=8.6 Hz), 7.37(1H, dd, J=8.6 Hz, 2.2 Hz), 7.40(1H, d, J=8.8 Hz), 7.52(1H, d, J=2.2 Hz), 7.65(1H, dd, J=8.8 Hz, 1.6 Hz), 7.68(1H, t, J=5.7 Hz), 8.55(1H, d, J=1.6 Hz), 12.20(1H, brs)

EXAMPLE 261 2-Chloro-8-(3,4-methoxydioxybenzyl)aminopyrido[2,3-d]-pyrimidine ##STR322##

66 mg of triethylamine and 89 mg of piperonylamine were added to a solution of 118 mg of 2,8-dichloropyrido[2,3-d]pyrimidine in 20 ml of tetrahydrofuran. The obtained mixture was stirred at room temperature for 16 hours, followed by the addition of water. The crystals thus precipitated were recovered by filtration, whereby 166 mg of the title compound was obtained.

molecular formula; C₁₅ H₁₁ ClN₄ O₂

yield(%); 89

m.p.(°C.); 200˜202

Mass m/e; 315 (M+1)

NMR δ (DMSO-d₆): 4.64(1H, d, J=5.6 Hz), 5.97(2H, s), 6.85(1H, d, J=8.0 Hz), 6.87(1H, d, J=8.0 Hz), 6.96(1H, s), 7.55(1H, dd, J=8.0 Hz, 4.4 Hz), 8.73(1H, dd, J=8.0 Hz, 1.6 Hz), 8.96(1H, dd, J=4.4 Hz, 1.6 Hz), 9.46(1H, t, J=5.6 Hz)

EXAMPLE 262 2-(4-Carboxypiperidino)-8-(3,4-methylenedioxybenzyl)aminopyrido[2,3-d]pyrimidine ##STR323## a) 2-4-ethoxycarbonylpiperidino)-8-(3,4-methylenedioxybenzylamino)pyrido[2,3-d]pyrimidine ##STR324##

41 mg of triethylamine add 190 mg of ethyl isonipecotate were added to a solution of 127 mg of 2-chloro-8-(3,4-methylenedioxybenzyl)aminopyrido[2,3-d]pyrimidine in 8 ml of tetrahydrofuran. The obtained mixture was refluxed for 2 hours, followed by the addition of water. The resulting mixture was extracted with chloroform twice. The organic layers were combined, dried over magnesium sulfate, and distilled to remove the solvent. The residue was purified by silica gel chromatography (with ethyl acetate) to give 175 mg of the title compound (in a yield of 100%).

b) 2-(4-carboxypiperidino)-8-(3,4-methylenedioxybenzyl)aminopyrido[2,3-d]pyrimidine ##STR325##

1.56 ml of 1N sodium hydroxide was added to a solution of 170 mg of 2-(4-ethoxycarbonylpiperidino)-8-(3,4-methylenedioxybenzyl)aminopyrido[2,3-d]-pyrimidine in 10 ml of ethanol. The obtained mixture was stirred at room temperature for 6 hours and neutralized by the addition of 1N hydrochloric acid and water. The crystals thus precipitated were recovered by filtration, whereby 121 mg of the title compound was obtained.

molecular formula; C₂₁ H₂₁ N₅ O₄

yield(%); 76

m.p.(°C.); 255˜256

Mass m/e; 408 (M+1)

NMR δ (DMSO-d₆); 1.39(2H, m), 1.80(2H, m), 2.51(1H, m), 3.01(2H, brt, J=11.2 Hz), 4.56(2H, d, J=5.6 Hz), 4.61(2H, brd, J=12.8 Hz), 5.94(2H, s), 6.82(1H, d, J=8.0 Hz), 6.84(1H, d, J=8.0 Hz), 6.93(1H, s), 7.03(1H, dd, J=8.0 Hz, 4.4 Hz), 8.38(1H, dd, J=8.0 Hz, 1.6 Hz), 8.61 (1H, dd, J=4.4 Hz, 1.6 Hz), 8.70(1H, t, J=5.6 Hz), 12.16(1H, brs)

EXAMPLE 263 5-Chloro-2-methanesulfonyl-1-(3,4-methylenedioxybenzyl)benzimidazole ##STR326##

8.89 g of 6-chloro-2-mercaptobenzimidazole was dissolved in 150 ml of dimethylformamide, followed by the addition of 6.65 g of potassium carbonate and 6.15 g of methyl iodide under cooling with ice. The obtained mixture was stirred at that temperature for 50 minutes, followed by the addition of water. The resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated in a vacuum to give crude 6-chloro-2-methylthiobenzimidazole.

This crude product was dissolved in 100 ml of methylene chloride, followed by the addition of 17.3 g of 80% m-CPBA under cooling with ice. The obtained mixture was stirred at room temperature overnight, followed by the addition of 7 g of sodium thiosulfate. The resulting mixture was stirred at room temperature for 30 minutes, followed by the addition of water. The organic layer was recovered, dried and subjected to silica gel column chromatography to give 10 g of 6-chloro-2-methanesulfonylbenzimidazole.

2.3 g of the 6-chloro-2-methanesulfonylbenzimidazole was dissolved in 30 ml of dimethylformamide, followed by the addition of 480 mg of 60% sodium hydride and 2.04 g of piperonyl chloride under cooling with ice. The obtained mixture was maintained at 80° C. by heating for 4 hours, allowed to stand overnight and filtered to remove insolubles. The filtrate was concentrated in a vacuum and subjected to silica gel column chromatography to give the title compound.

molecular formula; C₁₆ H₁₃ ClN₂ O₄ S

yield(%); 25

m.p.(° C.); 129-131

Mass m/e; 365 (MH⁺)

NMR δ (CDCl₃); 3.48(3H, s), 5.64(2H, s), 5.9t (2H, s), 6.73˜6.76(3H, m), 7.27(1H, d, J=8.8 Hz), 7.31 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.80(1H, d, J=2.0 Hz)

EXAMPLE 264 6-Chloro-2-methanesulfonyl-1-(3,4-methylenedixoybenzyl)benzimidazole ##STR327##

The title compound was obtained by further elution after the elution of the 5-chloro-2-methanesulfonyl-1-(3,4-methylene-dixoybenzyl)benzimidazole in EXAMPLE 263.

molecular formula; C₁₆ H₁₃ ClN₂ O₄ S

yield(%); 22

m.p. (° C.); 140˜142

Mass m/e; 365 (MH⁺)

NMR δ (CDCl₃);

3.48(3H, s), 5.62(2H, s), 5.93(2H, s), 6.73˜6.77(3H, m), 7.32(1H,d,J=8.4 Hz), 7.33(1H, d, J=1.2 Hz), 7.74(1H, dd, J=8.4 Hz, 1.2 Hz)

EXAMPLE 265

5-Chloro-2-methoxy-1-(3,4-methylenedioxybenzyl)-benzimidazole. ##STR328##

448 mg of a mixture comprising 5-chloro-2-sulfonylmethyl-1-(3,4-methylenedioxybenzyl)benzimidazole and 6-chloro-2-sulfonylmethyl-1-(3,4-methylenedioxybenzyl)benzimidazole was dissolved in 20 ml of methanol, followed by the addition of 10 ml of 28% sodium methoxide. The obtained mixture was heated under reflux for 1.5 hours, cooled with ice, neutralized with 104 aqueous hydrochlic acid, and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated in a vacuum. The residue was subjected to silica gel column chromatography to give the title compound.

molecular formula; C₁₆ H₁₃ ClN₂ O₃

yield(4); 31

m.p.(° C.); 117-118

Mass m/e; 317 (MH⁺)

NMR δ (CDCl₃): 4.21(3H, s), 5.01 (2H, s), 5.92(2H, s), 6.65(1H, d, J=1.6 Hz), 6.68(1H, dd, J=8.0 Hz. 1.6 Hz), 6.73(1H, d, J=8.0 Hz), 6.96(1H, d, J=8.4 Hz), 7.05(1H, dd, J=8.4 Hz, 2.0 Hz). 7.51 (1H, d, J=2.0 Hz)

EXAMPLE 266 6-Chloro-2-methoxy-]-(3,4-methylenedioxybenzyl)benzimidazole ##STR329##

The title compound was obtained by further elution after the elution of the 5-chloro-2-methoxy-1-(3,4-methylenedioxybenzyl)benzimidazole in Example 265.

molecular formula; C₁₆ H₁₃ ClN₂ O₃

yield(%); 26

m.p.(° C.); 133˜134

Mass m/e; 317 (MH⁺)

NMR δ (CDCl₃); 4.21(3H, s), 4.99(2H, s), 5.92(2H.s), 6.65(1H.d.J=1.6 Hz), 6.68(1H, dd, J=8.0 Hz. 1.6 GHz), 6.74(1H, d, J=8.0 Hz). 7.05(1H, d, J=1.6 Hz). 7.10(1H, dd, J=8.8 Hz, 1.6 Hz), 7.43(1H, d, J=8.8 Hz)

EXAMPLE 267 to 280

The following compounds were prepared in a similar manner to those of Examples 263 to 266.

EXAMPLE 267 1-(3,4-Methylenedioxybenzyl)benzimidazole ##STR330## molecular formula; C₁₅ H₁₂ N₂ O₂ yield(%); 34

m.p.(° C.); 107˜108

Mass m/e; 253 (MH⁺)

NMR δ (CDCl₃); 5.23(2H. s), 5.92(2H, s). 6.63(1H. d, J=1.6 Hz). 7.23˜7.32 (3H, m), 6.70(1H, dd. J=8.0 Hz, 1.6 Hz). 6.76(1H. d, J=8.0 Hz), 7.23˜7.32(3H, m), 7.80˜7.83(1H, m). 7.92(1H, s)

EXAMPLE 268 1-(2-Propoxybenzyl)benzimidazole ##STR331## molecular formula; C₁₇ H₁₈ N₂ O yield(%); 89

m.p.(° C.); 85-86

Mass m/e; 267 (MH⁺)

NMR δ (CDCl₃); 1.02(3H, t, J=7.4 Hz, 1.78˜1.86(2H, m), 3.95(2H, t, J=6.6 Hz), 5.35(2H, s), 6.86˜6.90(2H, m), 7.06˜7.09(1H, m), 7.23˜7.28(3H, m), 7.40˜7.43(1H, m), 7.79˜7.82(1H, m), 7.99(1H, s)

EXAMPLE 269 2-(3,4-Methylenedioxybenzyl)benzimidazole ##STR332## molecular formula; C₁₅ H₁₂ N₂ O₂ yield(%); 62

m.p.(° C.); 143˜146

Mass m/e; 253 (MH⁺)

NMR δ (DMSO-d₆); 4.43(2H, s). 5.99(2H, s), 6.89˜6.94(2H. m), 7.09(1H, s), 7.48˜7.52(2H, m), 7.72˜7.76(2H, m)

EXAMPLE 270 1-(3,4-Methylenedioxybenzyl)-6-metboxybenzimidazole ##STR333## molecular formula; C₁₆ H₁₄ N₂ O₃ yield(%); 70

m.p.(° C.); 184˜135

Mass m/e; 288 (M+1)⁺

NMR δ(CDCl₃); 3.82(3H, s), 5.21 (2H, s), 5.95(2H, s), 6.64(1H. d. J=1.8 Hz), 6.71 (1H. dd, J=7.6 Hz. 1.8 Hz), 6.75(1H, d. J=2.4 Hz), 6.78(1H. d. J=7.6 Hz, 6.93(1H, dd. J=8.8 Hz, 2.4 Hz). 7.70(1H, d. J=8.8 Hz). 7.90(1H, s)

EXAMPLE 271 1-(2-Chloro-4,5-methylenedioxybenzyl)-6-methoxybenzimidazole ##STR334## molecular formula; C₁₆ H₁₃ ClN₂ O₃ yield(%); 81

m.p. (° C.); 108-109

Mass m/e; 317 (M+1)⁺

NMR δ (CDCl₃); 3.84(3H, s). 5. 322(2H. s), 5.97(2H, s), 6.40(1H. s), 6.80(1H, s). 6.91 (1H, s), 6.95(1H, d. J-8.8 Hz), 7.72(1H. d, J=8.8 Hz), 7.96(1H, s)

EXAMPLE 272 1-[2-(3,4-Methylenedioxyphenyl)ethyl]-6-methoxybenzimidazole ##STR335## molecular formula; C₁₇ H₁₆ N₂ O₃ yield(%); 69

m.p.(° C.); oily substance

Mass m/e; 297 (M+1)⁺

NMR δ (CDCl₃); 3.04(2H, t, J=6.8 Hz). 3.87(3H, s). 4.31 (2H. t. J=6.8 Hz), 5.93(2H, s), 6.43(1H. dd, J-8.0 Hz. 2.0 Hz). 6.52(1H, d, J=2.0 Hz). 6.68(1H. d. J=8.0 Hz), 6.77(1H, d, J-2.4 Hz). 6.92(1H. dd. J=8.8 Hz, 2.4 Hz), 7.57(1H, s), 7.67(1H. d, J=8.8 Hz)

EXAMPLE 273 6-Chloro-1-(3,4-methylenedioxybenzyl)benzimidazole ##STR336## molecular formula; C₁₅ H₁₁ N₂ O₂ m.p. (° C.); 122-123

Mass m/e; 287 (MH⁺)

NMR δ (CDCl₃); 5.18(2H, s), 5.94-(2H.s), 6.61(1H.d.J=1.2 Hz), 6.68(1H. dd, J=8.0 Hz. 1.2 Hz). 6.77(1H, d. J=8.0 Hz), 7.22˜7.40(2H, m 7.71 (1H, d. J=8.8 Hz), 7.90(1H, s)

EXAMPLE 274 5-Chloro-1-(3,4-methylenedioxybenzyl)benzimidazole ##STR337## molecular formula; C₁₅ H₁₁ ClN₂ O₂ yield(%); 83

m.p.(° C.); 113-114

Mass m/e; 287 (MH⁺)

NMR δ (CDCl₃): 5.20(2H. s). 5.93(2H. s), 6.60(1H. d, J=1.6 Hz), 6.67(1H. dd, J=7.6 Hz. 1.6 Hz). 7.76(1H. d, J=7.6 Hz). 7.18˜7.20 (2H,m). 7.78(1H, s), 7.93(1H, s)

EXAMPLE 275 6-Chloro-[3-(3,4-methylenedioxyphenyl)propyl]-benzimidazole ##STR338## molecular formula; C₁₇ H₁₅ ClN₂ O₂ yield(%); 40

m.p. (° C.); 107-109

Mass m/e; 315 (MH⁺)

NMR δ (CDCl₃); 2.13˜2.21(2H.m). 2.54(2H, t, J=7.4 Hz), 4.11 (2H, t. J=7.2 Hz), 5.94(2H, s), 6.59(1H, dd, J=8.0 Hz. 1.6 Hz). 6.64(1H. d. J=1.6 Hz), 6.75(1H, d, J=8.0 Hz), 7.24(1H, dd. J=8.4 Hz. 2.0 Hz). 7.31 (1H, d, J=2.0 Hz), 7.71 (1H, d, J=8.44 Hz), 7.84(1H, s)

EXAMPLE 276 6-Chloro-2-formyl-1-(3,4-methylenedioxybenzyl)-benzimidazole ##STR339## molecular formula; C₁₆ H₁₁ ClN₂ O₃ yield (%); 55

m.p.(° C.); 120˜122

Mass m/e; 315 (MH⁺)

NMR δ (CDCl₃); 5.71 (2H, s), 5.93(2H, s), 6.64(1H, d, J=1.6 Hz). 6.70(1H, dd. J=7.6 Hz, 1.6 Hz). 6.75(18, d, J=7.6 Hz), 7.36(1H, dd, J=8.8 Hz, 2.0 Hz). 7.46(1H. d. J=2.0 Hz), 7.86(1H, d, J=8.8 Hz), 10.11(1H.s)

EXAMPLE 277 2-Amino-6-chloro-1-(3,4-methylenedioxybenzyl)-benzimidazole ##STR340## molecular formula; C₁₅ H₁₂ ClN₃ O₂ yield(%); 10

m.p.(° C.); 223-224

Mass m/e; 302 (MH⁺)

NMR δ (DMSO-d₆): 5.13(2H, s), 5.95(2H, s), 6.68˜6.71(3H, m). 6.77(1H, d, J=1.6 Hz). 6.84(1H, d. J=7.6 Hz), 6.90(1H. dd, J=8.4 Hz. 2.4 Hz), 7.07 (1H. d. J=8.4 Hz), 7.18(1H, d, J=2.4 Hz)

EXAMPLE 278 6-chloro-2-(imidazol-1-yl)-1-(3,4-methylenedioxybenzyl)benzimidazole ##STR341## molecular formula; C₁₈ H₁₃ ClN₄ O₂ yield(%); 41

m.p.(° C.); 127˜129

Mass m/e; 353 (MH⁺)

NMR δ (CDCl₃); 5.20(2H, s), 5.97(2H, s), 6.48˜6.50(2H, m), 6.76(1H, d.J=7.2 Hz). 7.23˜7.35(4H, m), 7.72(1H, d, J=8.4 Hz), 7.89(1H, s)

EXAMPLE 279 2-(4-Carboxypiperidino)-5-chloro-1-(3,4-methyleriedioxybenzyl)benzimidazole ##STR342## molecular formula; C₂₁ H₂₀ ClN₃ O₄ yield(%); 84

m.p.(° C.); 201-202

Mass m/e; 414 (MH⁺)

NMR δ (CDCl₆); 1.64˜1.77(2H, m). 1.84˜1.90(2H, m), 2.40˜2.46(1H.m). 2.92˜3.00(2H.m), 3.43˜3.47(2H.m). 5.15(2H, s), 5.96(2H, s), 6.60(1H, dd, J=8.0 Hz. 1.6 Hz). 6.72(1H, d, J=1.6Hz), 6.82(1H, d, J=8.0 Hz), 7.03(1H, dd. J=8.4 Hz. 2.0 Hz). 7.18(1H, d. J=8.4 Hz), 7.42(1H. d. J=2.0 Hz)

EXAMPLE 280 2 -(4-Carboxypiperidino)-6-chloro-1-(3,4-methylenedioxybenzyl)benzimidazole ##STR343## molecular formula; C₂₁ H₂₀ ClN₃ O₄ m.p.(° C.); amorphous

Mass m/e; 414 (MH⁺)

NMR δ (DMSO-d₆ ; 1.70˜1.79(2H.m). 1.80˜1.89(2H, m), 2.31˜2.42(1H.m). 2.90˜2.97(2H. m). 3.39˜3.45 (2H, m), 5.15(2H. s). 5.96(2H, s), 6.61 (1H. d. J-8.0 Hz), 6.73(1H, s), 6.83(1H. d. J=8.0 Hz). 7.06(1H. dd, J=8.4 Hz, 2.0 Hz). 7.30(1H, d. J=2.0 Hz). 7.30(1H, d, J=8.4 Hz)

EXAMPLES 281 to 291

The following compounds were prepared in a similar manner to those of Examples 88 to 94.

EXAMPLE 281 2-(4-Carboxypiperidino)-4-(3,5-dichloro-4-methoxybenzylamino)-6-cyanoquinazolime ##STR344## molecular formula; C₂₃ H₂₁ C₁₂ N₅ O₃ yield(%); 98

m.p.(° C.); 255˜256 (dec.)

Mass m/e; 486

NMR δ (DMSO-d₆): 1.36(2H. brm), 1.80(2H, brm). 2.52(1H, m), 3.03(2H. m), 3.78(3H. s). 4.59(2H. d, J=6.0 Hz), 4.59(2H, brm). 7.29(1H. d. J=8.8 Hz), 7.90(2H, s), 7.75(1H. dd, J=8.8 Hz, 1.6 Hz). 8.53(1H. d, J=1.6 Hz). 8.85(1H, brt, J=6.0 Hz). 12.18(1H, brs)

EXAMPLE 282 2,6-Dichloro-4-(4-etboxycarbonylpiperidino)quinazoline ##STR345## molecular formula; C₁₆ H₁₇ Cl₂ N₃ O₂ yield(%); 100

m.p.(° C.); 101-103

Mass m/e; 354 (M+1)

NMR δ (CDCl₃); 1.30(3H. t. J=7.2 Hz). 1.99(2H, m). 2.14(2H, m), 2.69(1H.m), 3.35(2H. dr. J=11.2 Hz. 2.4 Hz). 4.20(2H. q. J=7.2 Hz), 4.31 (2H, dr, J=13.6 Hz, 3.6 Hz). 7.67(1H, dd, J=8.8 Hz. 2.2 Hz), 7.76(1H. d. J=8.8 Hz), 7.79(1H, d, J=2.2 Hz)

EXAMPLE 283 2-[N-[2-(2-Pyridyl)ethyl]methylamino]-4-(3,4-methylenedioxybenzyl)lamino-6-chloroquinazoline dihydrochloride ##STR346## molecular formula; C₂₄ H₂₂ ClN₅ O₂ ·2HCl yield(%); 94

m.p.(° C.); 234-236 (dec.)

Mass m/e; 448 (M+1)⁺

NMR δ (DMSO-d₆); 3.2˜3.3(5H, br), 4.12(2H, br). 4.61(2H, br), 5.97(2H.s). 6.82(1H. brd). 6.88(1H. brd), 7.00(1H. s), 7.74(2H, br), 7.86(1H. dd, J=9.2 Hz, 2.0 Hz), 8.01 (1H. br). 8.26(1H. br), 8.57(1H.d.J=2.0 Hz), 8.74(1H. br). 10.16(1H. brs), 12.12(1H, brs)

EXAMPLE 284 2-(4-Carboxypiperidino)-4-3,4-dihydroxybenzyl)amino-6-chloroquinazoline ##STR347## molecular formula; C₂₁ H₂₁ ClN₄ O₄ yield(%); 95

m.p.(° C.); 216-218 dec.)

Mass m/e; 429 (MH⁺)

NMR δ (DMSO-d₆); 1.38˜1.47 (2H. m). 1.80˜1.84(2H.m), 2.44˜2.49(1H, m). 2.93˜3.00(2H. m), 4.48(2H. d, J=5.6 Hz), 4.57˜4.61 (2H,m), 6.60˜6.65(2H, m). 6.74(1H, d. J=1.6 Hz), 7.24(1H. d. J=8.8 Hz), 7.46(1H, dd, J=8.8 Hz, 2.0 Hz), 8.15(1H, d, J=2. OHz), 8.48(1H, brs). 8.675(1H, s), 8.75(1H, s), 12.14(1H, brs)

EXAMPLE 285 2,6-Dichloro-4-(5-hydroxypentyl)aminoquinazoline ##STR348## molecular formula; C₁₃ H₁₅ Cl₂ N₃ O yield(%); 82

m.p.(° C.); 134-135

Mass m/e; 300 (M+1)⁺

NMR δ (CDCl₃): 1.58(2H. m). 1.65(2H. m), 1.76(2H. m), 8.88(2H, m), 3.66(2H, m), 7.61(1H. dd, J=8.8 Hz 2.4 Hz) 7.67(1H,d J=8.8 Hz)7.85(1H, brs), 8.20(1H, d, J=2.4 Hz)

EXAMPLE 286 2-(4-Carboxypiperidino)-4-(5-nitroxypentyl)amino-6-chloroquinazoline ##STR349## molecular formula; C₁₉ H₂₄ ClN₅ O₅ yield(%); 80

m.p.(° C.); 176˜179 (dec.)

Mass m/e; 438 (MH⁺)

NMR δ (DMSO-d₆); 1.34˜2.00(10H,m), 2.57˜2.64(1H, m), 3.18˜3.59(4H, m), 4.44˜4.58(4H, m), 7.72˜7.86(2H, m), 8.39˜8.41(1H, m), 12.31(2H, brs)

EXAMPLE 287 2-(Carboxymethyl)methylamino-4-(3-pyridylmethyl)-amino-6-chloroquinazoline ##STR350## molecular formula; C₁₇ H₁₆ ClN₅ O₂ yield(%); 97

m.p.(° C.); 222-223

Mass m/e; 358 (M+1)

NMR δ (DMSO-d₆);

3.10(3H.s). 4.22(2H. brs). 4.63(2H. brs). 7.31(2H, m), 7.48(1H. m). 7.72(1H, m), 8.14(1H, d. J=2.4 Hz), 8.59(1H. m), 8.66(1H, brs.)

EXAMPLE 288 2-[N-(3-Carboxypropyl)-N-methylamino]-4-(3-pyridylmethyl)amino-6-chloroquinazoline ##STR351## molecular formula; C₁₉ H₂₀ ClN₅ O₂ yield(%); 41

m.p.(° C.); 110-112

Mass m/e; 386 (M+1)

NMR δ (DMSO-d₆); 1.67(2H. brs). 2.09(2H. m). 3.02(3H. s). 3.53(2H, t, J=6.8 Hz), 4.67(2H, d, J=5.6 Hz). 7.24(2H, d, J=8.8 Hz). 7.31 (1H. dd, J=8.0 Hz, 4.8 Hz), 7.47(1H, dd, J=8.8 Hz. 2.0 Hz), 7.73(1H, d, J=8.0 Hz), 8.13(1H. d. J=2.0 Hz), 8.41(1H. d,J=4.8 Hz). 8.58(1H, s), 8.62(1H. brs), 12.04(1H, brs)

EXAMPLE 289 2-(4-Carboxypiperidino)-4-(2-pyridylmethyl)amino-6-chloroquinazoline ##STR352## molecular formula; C₂₀ H₂₀ ClN₅ O₂ yield(%); 92

m.p.(° C.); 235-237

Mass m/e; 398 (M+1)

NMR δ (DMSO-d₆); 1.25˜1.45(2H. m). 1.71˜1.83(2H, m). 2.45˜2.54 (1H, m). 2.93˜3.10(2H. m), 4.37˜4.48(2H, m). 4.77(2H, d, J=5.5 Hz). 7.25(1H, dd, J=7.7 Hz,5.0 Hz), 7.37(1H, d, J=7.7 Hz), 7.48(1H, brs), 7.63(1H, brs), 7.73(1H, td. J=7.7 Hz, 1.6 Hz), S. 34(1H, brs), 8.51 (1H, brd, J=5.0 Hz), 12.23(1H. brs)

EXAMPLE 290 2-(4-Carboxypiperidino)-4-(3-pyridylmethyl)amino-6-chloroquinazoline ##STR353## molecular formula; C₂₀ H₂₀ ClN₅ O₂ yield(%); 93

m.p.(° C.); >250

Mass m/e; 998 (M+1)

NMR δ (DMSO-d₆); 1.45˜1.60(2H, m), 1.84˜1.97(2H, m), 2.58˜2.68(1H, m), 3.25˜8.45(2H. m). 4.45˜4.54(2H, m), 4.80(2H, d, J=5.7 Hz), 7.41 (1H, dd, J=7.9 Hz, 4.8 Hz), 7.82(1H, dd, J=9.0 Hz, 2.0 Hz), 7.86˜7.96(2H, m), 8.50(1H, d, J=4.8 Hz), 8.55(1H,d,J=1.6 Hz), 8.69(1H, s)

EXAMPLE 291 2-(4-Carboxypiperidino)-4-(4-pyridylmethyl)amino-6-chloroquinazoline ##STR354## molecular formula; C₂₀ H₂₀ ClN₅ O₂ yield(%); 89

m.p.(° C.); 167˜168

Mass m/e; 398 (M+1)

NMR δ (DMSO-d₆): 1.24˜1.36(2H, m), 1.68˜1.77(2H, m), 2.40˜2.49(1H.m), 2.85˜2.96(2H.m). 4.42˜4.50(2H, m), 4.66(2H, d, J=5.7 Hz), 7.28(1H, d, J=9.0 Hz), 7.34(2H, d. J=6.0 Hz), 7.51(1H. dd, J=9.0 Hz, 2.4 Hz). 8.18(1H. d. J=2.4 Hz), 8.47(2H. d, J=6.0 Hz). 8.74(1H, t, J=5.7 Hz)

EXAMPLE 292 2-(6-Nitroxyhexyloxy)-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazoline ##STR355##

860 mg of 2-(6-hydroxyhexyloxy)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was dissolved in 15 ml of pyridine, followed by the addition of 570 mg of methyl chloride under cooling with ice. The obtained mixture was stirred for 10 hours, followed by the addition of water. The resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to give 1.2 g of crude 2-(6-tosyloxyhexyloxy)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline.

3 g of sodium iodide and 80 ml of dimethylformamide were added to the crude product. The obtained mixture was maintained at 60° C. by heating for one hour, followed by the addition of water. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography to give 450 mg of 2-(6-iodohexyloxy)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline.

410 mg of the 2-(6-iodohexyloxy)-4-(3,4-methylenedioxybenzyl)amino-B-chloroquinazoline was suspended in 15 ml of acetonitrile, followed by the addition of 900 mg of silver nitrate. The obtained mixture was maintained at 60° C. by heating for one hour, followed by the addition of water and ethyl acetate. The resulting mixture was filtered through Celite to remove insolubles. The organic layer was recovered, dried and subjected to silica gel column chromatography to give 340 mg of the title compound.

molecular formula; C₂₂ H₂₃ ClN₄ O₆ (474.5)

yield(%); 95

m.p.(° C.); 121˜122

Mass; 475 (MH⁺)

NMR δ (CDCl₃); 1.42-1.59 (4H, m), 1.70˜1.89 (4H, m), 4.43 (4H, q, J=6.8 Hz), 4.73 (2H, d, J=4.4 Hz), 5.95 (2H, s), 6.28 (1H, br), 6.77 (1H, d, J=8.0 Hz), 6.83 (1H, d, J=8.0 Hz), 6.85 (1H, s), 7.54 (1H, d, J=8.8 Hz), 7.58 (1H, d, J=8.8 Hz), 7.66 (1H, s)

EXAMPLE 293 Sodium 2-(3-sulfoxypropoxy)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR356##

1 g of 2-(3-hydroxypropoxy)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline and 540 mg of sulfur trioxide/trimethylamine complex were suspended in 10 ml of pyridine. The obtained suspension was stirred at room temperature overnight, followed by the addition of ethyl acetate. The crystals thus precipitated were recovered by filtration, suspended in methanol and dissolved therein by the addition of 1N sodium hydroxide. Ether was added to the obtained solution to precipitate crystals. The crystals were recovered by filtration, whereby 400 mg (32%) of the title compound was obtained.

molecular formula; C₁₉ H₁₇ ClN₃ NaO₇ S (489.5)

yield(%); 32

m.p.(° C.); 190-192 (dec.)

Mass; 490 (MH⁺)

NMR δ (DMSO-d₆); 1.90˜1.95 (2H, m), 3.82 (2H, t, J=6.4 Hz), 4.28 (2H, t, J=6.8 Hz), 4.61 (2H, d, J=5.6 Hz), 5.95 (2H, s), 6.84 (2H, s), 6.98 (1H, s), 7.50 (1H, d, J=8.8 Hz), 7.64 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.84 (1H, d, J=2.4 Hz), 8.79 (1H, t, J=1.6 Hz)

EXAMPLE 294 2-(4-Ethoxycarboxypiperidino)carbonyl-4-(3,4-methylene dioxybenzylamino-6-chloroqnlinazoline hydrochloride ##STR357##

A solution of 0.50 ml (3.3 mmol) of diethyl cyanophosphate in 3 ml of dimethylformamide and 0.50 ml (3.6 mmol) of triethylamine were dropped, in this order, into a solution of 0.78 g (2.2 mmol) of 2-carboxy-4-(3,4-methylenedixoybenzyl)amino-6-chloroquinazoline and 0.50 g (3.2 mmol) of ethyl isonipecotate in 7 μl of dimethylformamide under cooling with ice and stirring. The obtained mixture was stirred under cooling with ice for 30 minutes and thereafter at room temperature for 3 hours, followed by the addition of water. The resulting mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled in a vacuum to remove the solvent. The residue was recrystallized from hydrochloric acid/ethanol/ether to give 0.96 g of the title compound.

molecular formula; C₂₅ H₂₅ ClN₄ O₅ ·HCl

yield(%); 82

m.p.(° C.); 205-206 (dec.)

Mass m/e; 497 (M+1)⁺

NMR δ (DMSO-d₆); 1.18(3H. t, J=7.2 Hz). 1.51(2H, m), 1.70(1H.m), 1.95(1H.m). 2.66(1H.m) 3.02(1H.m), 3.11(1H, m). 3.62(1H.m). 4.08(2H, q, J=7.2 Hz), 4.31(1H.m). 4.71(1H. dd. J=14.9 Hz, 6.0 Hz), 4.78(1H, dd. J=14.9 Hz, 6.0 Hz), 5.97(2H, s). 6.84(1H. d. J=8.0 Hz), 6.87(1H. dd, J=8.0 Hz, 1.2 Hz). 6.97(1H, d.J=1.2 Hz). 7.82(1H. d. J=9.2 Hz), 7.97(1H, dd, J=9.2 Hz. 2.0 Hz), 8.67(1H, d, J=2.0 Hz). 10.13(1H, brs)

EXAMPLE 295 2-[N-(2-Sulfoethyl)carbamoyl]-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline hydrochloride ##STR358##

0.60 ml (3.8 mmol) of diethyl cyanophosphate and 0.90 ml (6.4 mmol) of triethylamine were dropped, in this order, into a solution of 0.50 g (1.4 mmol) of 2-carboxy-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline and 0.28 g (1.9 mmol) of sodium 2-aminoethanesulfonate in 15 ml of dimethylformamide under cooling with ice and stirring. The obtained mixture was stirred at room temperature for several days, followed by the addition of 10 ml of 1N hydrochloric acid and water. The crystals thus precipitated were recovered by filtration, washed with water and air-dried to give 0.61 g of the title compound.

molecular formula; C₁₉ H₁₇ ClN₄ O₆ S·HCl

yield(%); 93

NMR δ (DMSO-d₆); 2.76(2H, T, J=6.4 Hz), 3.67(2H, q. J=6.4 Hz). 5.01 (2H, d, J=5.6 Hz), 5.99(2H. s), 6.88(1H, d. J=7.6 Hz). 7.05(1H, dd, J=7.6 Hz, 1.6 Hz), 7.11(1H, d. J=1.6 Hz), 8.09(1H, dd, J=8.8 Hz, 2.0 Hz), 8.13(1H, d. J=8.8 Hz). 8.68(1H, d, J=2.0 Hz). 9.97(1H. t, J=5.6 Hz), 10.55(1H, brs)

EXAMPLE 296 2-(4-cis-Carboxycyclohexyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR359## a) 2-(4-Ethoxycarbonylcyclohexylcarbonyl)amino-5-chlorobenzamide

1.5 g of 4-ethoxycarbonyleyclohexanecarbonyl chloride was added to a mixture comprising 1.23 g of 2-amino-5-chlorobenzamide hydrochloride, 3 ml of N,N-diisopropylethylamine and 100 ml of tetrahydrofuran at room temperature. The obtained mixture was reacted at room temperature overnight, followed by the addition of water. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated. The residue was subjected to silica gel chromatography with 30 to 35% ethyl acetate/hexane to give 1.5 g of the title compound (as a cis/trans mixture).

b) 2-(4-Ethoxyearbonylcyclohexyl)-6-chloroquinazolon-4-one

1.3 g of the compound prepared in the step (a) was suspended in 20 ml of ethanol. 320 mg of potassium t-butoxide was added to the obtained suspension in three portions at room temperature. The resulting mixture was reacted at room temperature overnight. The reaction mixture was partially concentrated, followed by the addition of water and 3.5 ml of 1N hydrochloric acid in this order. The crystals thus precipitated were recovered by filtration, washed with water, and vacuum-dried over phosphorus pentaoxide to give 1.16 g of the title compound (as a cis/trans mixture).

c) 2-(4-cis-Ethoxycarboxylcyclohexyl)-4,6-dichloroquinazoline

20 ml of phosphorus oxychloride was added to 1.0 g of the compound prepared in the step (b). The obtained mixture was heated under reflux for 2 hours and concentrated. 50 ml of chloroform was added to the residue to form a solution, which was poured into a saturated aqueous solution of sodium hydrogen-carbonate cooled with ice. The chloroform layer was recovered and the aqueous layer was extracted with 30 ml of chloroform. The chloroform layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and filtered through a silica gel bed. The silica gel was washed with 104 ethyl acetate/hexane. The washings and the filtrate were combined and concentrated. The residue was subjected to silica gel column chromatography with 5% ethyl acetate/hexane to give 145 mg of the title compound.

NMR δ (CDCl₃); 1.28(3H. t. J=7.2 Hz), 1.69˜1.78(2H, m). 1.92˜2.02(2H, m). 2.05˜2.21(4H, m). 2.61˜2.68(1H.m), 3.05˜3.13(1H.m). 4.17(2H. q. J=7.2 Hz), 7.83(1H, dd, J=9.2 Hz, 2.4 Hz). 7.94(1H. d. J=9.2 Hz), 8.19(1H. d. J=2.4 Hz)

Simultaneously, 470 mg of 2-(4-trans-ethoxycarbonylcyclohexyl)-4,6-dichloroquinazoline was obtained as a more highly polar component.

NMR δ (CDCl₃); 1.28(3H, t, J=7.2 Hz), 1.57˜1.69(2H. m). 1.71˜1.84(2H, m), 2.13˜224(4H, m), 1.41(1H, tt, J=12.2 Hz. 3.5 Hz), 2.99(1H, tt, J=12.2 Hz, 3.5 Hz). 4.15(2H, q, J=7.2 Hz), 7.84(1H. dd, J=9.2 Hz, 2.4 Hz). 7.94(1H, d, J=9.2 Hz). 8.20(1H. d. J=2.4 Hz)

d) 2-(4-cis-Ethoxycarbonylcyclohexyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

A mixture comprising 145 mg of the compound prepared in the step (c), 80 mg of 3,4-methylenedioxybenzylamine, 20 μl of triethylamine and 5 ml of isopropyl alcohol was maintained at 80° C. for 3 hours to conduct a reaction. The reaction mixture was concentrated and extracted with ethyl acetate/water. The ethyl acetate layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography with 154 ethyl acetate/hexane to give 190 mg of the title compound.

NMR δ (CDCl₃); 1.25(3H, t, J=7.2 Hz), 1.66˜1.75(2H, 2.05˜2.23(4H. m). 2.60˜2.66(1H, m), 2.85˜2.93(1H, m), 4.15(2H. q. J=7.2 Hz). 4.74(2H. d, J=5.6 Hz). 5.72(1H, t, J=5.6 Hz), 5.96(2H, s). 6.79(1H. d. J=8.0 Hz). 6.85˜6.90(2H, m). 7.58˜7.62(2H, m), 7.74(1H. d. J=9.6 Hz)

e) 2-(4-cis-Carboxycyclohexyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline.

25 ml of ethanol and 2 ml of a 1N aqueous solution of sodium hydroxide were added to the compound prepared in the step (d). The obtained mixture was maintained at 60° C. for 8 hours and thereafter heated under reflux for 3 hours to conduct a reaction. The reaction mixture was cooled to room temperature, followed by the addition of 2 ml of 1N aqueous hydrochloric acid. The resulting mixture was partially concentrated to precipitate crystals. The crystals were recovered by filtration, washed with water and diethyl ether, and vacuum-dried over phosphorus pentaoxide to give 138 mg of the title compound.

molecular formula; C₂₃ H₂₂ ClN₃ O₄

yield(%); 77

m.p. (° C.); 152˜153

Mass m/e; 440 (M+1)

NMR δ (DMSO-d₆) 1.54˜1.64 (2H, m), 1.66˜1.76(2H, m), 1.89˜2.02(4H, m), 2.69˜2.77(1H, m), 4.63(2H, d. J=5.6 Hz), 5.96(2H. s). 6.84(1H. d, J=8.0 Hz) 6.89(1H. dd, 3˜8.0 Hz, 1.6 Hz), 6.95(1H. d. J-1.6 Hz), 7.63(1H, d, J=8.8 Hz), 7.71 (1H. dd. J=8.8 Hz, 2.4 Hz), 8.36(1H. d, J=2.4 Hz), 8.71 (1H. t, J=5.6 Hz)

EXAMPLE 297 2-(4-trans-Carboxycyclohexyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR360## a) 2-(4-trans-Ethoxycarbonylcyclohexyl)-4-(3,4-methylenedioxybenzyl)amino

145 mg of the trans isomer prepared in the step (c) of EXAMPLE 296 was treated in a similar manner to that of the step (d) of EXAMPLE 296 to give 180 mg of the title compound.

NMR δ (CDCl₃); 1.27(3H. t, J=7.2 Hz). 1.54˜1.67(2H.m). 1.70˜1.83(2H. m), 2.08˜2.17(4H.m), 2.39(1H, tt, J=12.2 Hz, 3.2 Hz). 2.79(1H, tt, J=12.2 Hz. 3.2 Hz), 4.14(2H, q, J=7.2 Hz). 4.76(2H, d, J=5.5 Hz), 5.82(1H, t J=5.5 Hz), 5.96(2H, s), 6.79(1H.d.J=7.9 Hz), 6.86(1H. dd, J=7.9 Hz, 1.5 Hz). 6.90(1H. d, J=1.6 Hz). 7.59˜7.63(2H, m), 7.73(1H, d, J=7.9 Hz)

b) 2-(4-Trans-carboxycyclohexyl)-4-(3,4-methylenediooxybenzyl)amino-6-chloroquinazoline

The compound prepared in the step (a) was hydrolyzed in a similar manner to that of the step (e) of EXAMPLE 296 to give 163 mg of the title compound.

molecular formula; C₂₃ H₂₂ ClN₃ O₄

yield(%); 96

m.p.(° C.); 245˜246

Mass m/e; 440 (M+1)

NMR δ (DMSO-d₆): 1.38˜1.50(2H, m), 1.55˜1.68(2H, m), 1.94˜2.04(4H, m), 2.34(1H, tt, J=11.9 Hz, 3.1 Hz), 2.60(1H, tt. J=11.9 Hz, 3.1 Hz), 4.66(2H. d. J=5.7 Hz). 5.97(2H. s). 6.85(1H, d. J=8.1 Hz), 6.88(1H, dd, J=8.1 Hz, 1.5 Hz), G. 98(1H, d, J=1.5 Hz), 7.63(1H, d. J=9.0 Hz), 7.72(1H, dd, J=9.0 Hz, 2.4 Hz). 8.37(1H. d, J=2.4 Hz), 8.71 (1H, brt, J=5.7 Hz), 12.04(1H, s)

EXAMPLE 298 2-(4-trans-Carboxycyclohexyl)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline ##STR361## a) 4-(4-methoxycarbonylcyclohexanecarbonyl)amoinobenzene-1,3-dicarboxamide

5.1 g of 4-methoxyearbonylcyclohexanecarbonyl chloride was added to a mixture comprising 3.6 g of 4-aminobenzene-1,3-diearboxamide, 5 ml of N,N-dimethylaniline and 50 ml of tetrahydrofuran at room temperature. The obtained mixture was reacted as such overnight, followed by the addition of water. The crystals thus precipitated were recovered by filtration, washed with water and diethyl ether, and dried to give 5.77 g of the title compound.

b) 2-(4-Methoxycarbonylcyclohexyl)-6-carbamoylquinazolin-4-one

5.7 g of the compound prepared in the step (a) was suspended in 200 ml of methanol, followed by the addition of 1.84 g of potassium t-butoxide. The obtained mixture was reacted at room temperature overnight, followed by the addition of water. The resulting mixture was acidified with concentrated hydrochloric acid to precipitate crystals. The crystals were recovered by filtration, washed with water and diethyl ether, and dried to give 5.04 g of the title compound.

c) 2-(4-trans-Methoxycarbonylcyclohexyl)-4-chloro-6-cyanoquinazoline

A mixture comprising 2.0 g of the compound prepared in the step (b), 2.0 g of lithium chloride and 40 ml of phosphorus oxychloride was heated under reflux for 6 hours and filtered to remove insolubles. The filtrate was concentrated and the residue was subjected to silica gel column chromatography with 10% ethyl acetate/hexane, whereby the trans isomer was separated from the cis isomer. 180 mg of the title compound was obtained.

NMR δ (CDCl₃); 1.57˜1.70(2H.m), 1.72˜1.84(2H.m). 2.12˜2.26(4H, m), 2.43(H. tt, J=12.3 Hz, 3.2 Hz), 3.03(1H, tt, J=11.9 Hz,3.0 Hz). 3.71 (3H, s), 8.04(1H, dd, J=8.8 Hz, 1.6 Hz). 8.08(1H, dd, J=8.8 Hz. 0.5 Hz), 8.62(1H, dd. J=1.6 Hz. 0.5 Hz)

d) 2-(4-trans-Methoxycarbonylcyclohexyl]-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline

A mixture comprising 180 mg of the compound prepared in the step (c), 100 mg of 3,4-methylenedioxybenzylamine, 200 μl of triethylamine and 5 ml of isopropyl alcohol was maintained at 80° C. for one hour to conduct a reaction. The reaction mixture was concentrated and extracted with ethyl acetate/water. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography with 10% ethyl acetate/benzene to give 157 mg of the title compound.

NMR δ (CDCl₃); 1.55˜1.68(2H.m), 1.70˜1.82(2H.m). 2.10˜2.18(4H, m), 2.42(1H, tt,J=12.3 Hz, 3.2 Hz), 2.81(1H.tt,J=11.9 Hz. 3.0 Hz), 3.70(3H.s), 4.78(2H, d, J=5.5 Hz), 6.96(2H, s), 6.20(1H, t, J=5.5 Hz), 6.80(1H, d. J=7.9 Hz). 6.88(1H. dd, J=7.9 Hz, 1.6 Hz). 6.90(1H, d. J=1.6 Hz), 7.82(2H, s), 8.11(1H, s)

e) 2-(4-trans-Carboxylcyclohexyl)-4-(3,4-methylenedioxy benzyl)amino-6-cyanoquinazoline

A mixture comprising 157 mg of the compound prepared in the step (d) , 1 ml of a 1N aqueous solution of sodium hydroxide, 3 ml of methanol and 6 ml of tetrahydrofuran was reacted at room temperature for 24 hours. 1 ml of 1N hydrochloric acid and 5 ml of water were added to the reaction mixture in this order to precipitate crystals. The crystals were recovered by filtration, washed with water, and dried to give 138 mg of the title compound.

molecular formula; C₂₄ H₂₂ N₄ O₄

yield(%); 91

m.p.(° C.); 269˜270

Mass m/e; 431 (M+1)

NMR δ (DMSO-d₆); 1.38˜1.50(2H. m). 1.55˜1.68(2H. m). 1.95˜2.04(4H, m). 2.24(1H. tt, J=11.9 Hz, 3.1 Hz), 2.63(1H, tt, J=11.9 Hz. 3.1 Hz). 4.68(2H. d. J=5.7 Hz). 5.97(2H, s). 6.86(1H, d, J=7.9 Hz), 6.90(1H, dd. J=7.9 Hz, 1.5 Hz), 6.99(1H, d. J=t. 5 Hz). 7.71 (1H, d. J=8.8 Hz), 8.01(1H. dd, J=8.8 Hz. 1.6 Hz). 8.82(1H. d, J=1.6 Hz), 8.95(1H, t, J=5.7 Hz)

EXAMPLE 299 2-Carbamoylmethyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline ##STR362## a) 2-Ethoxycarbonylmethyl-4-(3,4-methylenedloxybenzyl)amino-6-chloroquinazoline

The title compound was prepared in a similar manner to that of EXAMPLE 296.

NMR δ (CDCl₃); 1.27(3H. t. J=7.1 Hz). 3.93(2H, s). 4.22(2H, q, J=7.1 Hz). 4.71 (2H, d. J=5.5 Hz), 5.83(1H, t, J=5.5 Hz), 5.96(2H. s), 6.78(1H, d, J=7.9 Hz), 6.85(1H. dd, J=7.9 Hz. 1.6 Hz). 6.89(1H, d, J=7.60˜7.65(2H, m), 7.74(1H. d, J=9.0 Hz)

b) 2-Carbamoylmethyl-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazoline

A mixture comprising 200 mg of the compound prepared in the step (a) and 20 ml of ethanol was cooled with ice. Ammonium gas was introduced into the resulting mixture to saturate the mixture therewith. The resulting mixture was gradually brought to room temperature and reacted for 3 days. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography with 0 to 20% ethanol/ethyl acetate to give 24 mg of the title compound.

EXAMPLE 300 2-(4-Cyanopiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. ##STR363##

75 ml of thionyl chloride and 150 ml of acetonitrile were added to 3.8 g (0.0086 mol) of 2-(4-carbamoylpiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazoline. The mixture thus obtained was heated under reflux for one hour. The reaction mixture was distilled under a reduced pressure to remove the solvent. A saturated aqueous solution of sodium hydrogencarbonate and triethylamine were added to the residue and the resultant mixture was etracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure to remove the solvent. The obtained residue was purified by a silica gel column chromatography (ethyl acetate-n-hexane) and recrystallized from chloroform-n-hexane to give 8.1 g of the title compound.

molecular formula; C₂₂ H₂₀ ClN₅ O₂

yield(%); 85

m.p.(° C.); 169˜170

NMR δ (CDCl₃); 1.88 (2H,m), 1.95 (2H, m), 2.87 (1H, m), 3.73 (2H, m), 4.25 (2H, m), 4.67 (2H, d, J=5.6 Hz), 5.65 (1H, t, J=5.6 Hz), 5.97 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.84 ((1H, dd, J=8.0 Hz, 1.6 Hz), 6.87 (1H, d, J=1.6 Hz), 7.39 (1H, d, J=8.8 Hz), 7.44 (1H, d, J=2.4 Hz), 7.46 (1H, dd, J=8.8 Hz, 2.4 Hz)

EXAMPLE 301 2-[4-(1H-tetrazol-5-yl)piperidino]-4-(3,4-methylemedioxybenzyl)amimo-6-chloroquinazoline hydrochloride ##STR364##

10 ml of toluene was added to a mixture comprising 0.50 g (0.0012 mol) of 2-(4-cyanopiperidlno)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline and 0.50 g (0.0024 mol) of trimethyl stannylazide. The mixture thus obtained was heated under reflux for two days. The reaction mixture was distilled under a reduced pressure to remove the solvent. The residue was suspended in 10 ml of ethanol, followed by the addition of 10 ml of 1N hydrochloric acid. The mixture thus obtained was stirred at room temperature for several hours. The mixture was filtered to recover the crystal. The crystal was washed with water and air-dried to give 0.60 g of the title compound.

molecular formula; C₂₂ H₂₁ ClN₈ O₂ ·HCl

yield(%); quantitative

m. p. (° C.); 212˜214

Mass m/e; 465 (M+1)⁺

NMR δ (DMSO-d₆); 1.80 (2H,m), 2.17 (2H, m), 3.45 (2H, m), 4.62 (2H, m), 4.69 (2H, d, J=5.6 Hz), 5.97 (2H, s), 6.86 (1H, d, J=7.6 Hz ), 6.91 ((1H, dd. J=7.6 Hz, 1.6 Hz), 7.01 (1H, d, J=1.6 Hz), 7.84 (1H, dd, J=8.8 Hz, 1.6 Hz), 7.88 (1H, d, J=8.8 Hz). 8.51 (1H, d, J=1.6 Hz), 10.13 (1H, brs), 12.28 (1H, brs)

EXAMPLE 302 2-(1H-tetrazol-5-yl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline hydrochloride ##STR365##

The title compound was prepared in a similar manner to that of EXAMPLE 301.

molecular formula; C₁₇ H₁₂ ClN₇ O₂ ·HCl

yield(%); 37

m.p.(° C.); 201-204 (dec.)

Mass m/e; 382 (MH)⁺

NMR δ (DMSO-d₆);

4.90 (2H, d, J=5.6 Hz), 5.97 (2H, s), 6.87 (1H, d, J=8.0 Hz), 6.98 ((1H, dd, J=8.0 Hz, 2.0 Hz), 7.11 (1H, d, J=2.0 Hz), 7.92-7.94 (2H, m), 8.60 (1H, d, J=1.6 Hz), 9.53 (1H, brs)

EXAMPLES 303 to 410

The following compounds were each prepared by any method described above.

EXAMPLE 303 2-Chloro-4-(3,4-methylenedloxybenzyl)amino-6-methoxy-7-cyclopentyloxyquinazoline ##STR366## molecular formula; C₂₂ H₂₂ ClN₃ O₄ yield(%); 88

m.p.(° C.); 176˜177

Mass; 428 (M+1)⁺

NMR δ (CDCl₃); 1.64 (2H, m), 1.82 (2H, m), 1.93 (2H, m), 2.02 (2H, m), 3.90 (3H, s), 4.74 (2H, d, J=5.6 Hz), 4.85 (1H, m), 5.72 (1H, t, J=5.6 Hz), 5.96 (2H, s), 6.79 (1H, d, J=7.6 Hz), 6.79 ((1H, s), 6.87 (1H, dd, J=7.6 Hz, 1.6 Hz), 6.90 (1H, d, J=1.6 Hz), 7.11 (1H, s)

                                      TABLE 7                                      __________________________________________________________________________      ##STR367##                                                                                                     m.p.                                                                              yield                                      Ex.                                                                               R.sup.3                                                                          R.sup.5       R.sup.6       (°C.)                                                                      (%)                                                                               Mass NMR             note               __________________________________________________________________________     304                                                                               Cl                                                                                ##STR368##                                                                                   ##STR369##                                                                                   ##STR370##                                                                       97                                                                                 ##STR371##                                                                          ##STR372##                        305                                                                               Cl                                                                                ##STR373##                                                                                   ##STR374##                                                                                   ##STR375##                                                                       97                                                                                 ##STR376##                                                                          ##STR377##                        __________________________________________________________________________

                                      TABLE 8                                      __________________________________________________________________________      ##STR378##                                                                                                      m.p.                                                                               yield                                    Ex.                                                                               R.sup.2                                                                           R.sup.5     R.sup.6         (°C.)                                                                       (%)                                                                               Mass                                                                               NMR            note               __________________________________________________________________________     306                                                                               CN                                                                                 ##STR379##                                                                                 ##STR380##                                                                                     ##STR381##                                                                        93                                                                                 ##STR382##                                                                         ##STR383##                       307                                                                               CN                                                                                 ##STR384##                                                                                 ##STR385##                                                                                     ##STR386##                                                                        44                                                                                 ##STR387##                                                                         ##STR388##                       __________________________________________________________________________

                                      TABLE 9                                      __________________________________________________________________________      ##STR389##                                                                                                      m.p.                                                                               yield                                    Ex.                                                                               R.sup.2                                                                          R.sup.5      R.sup.6         (°C.)                                                                       (%)                                                                               Mass NMR           note               __________________________________________________________________________     308                                                                               Cl                                                                                ##STR390##                                                                                  ##STR391##                                                                                     ##STR392##                                                                        99                                                                                 ##STR393##                                                                          ##STR394##                      309                                                                               Cl                                                                                ##STR395##                                                                                  ##STR396##     >250                                                                               17                                                                                 ##STR397##                                                                          ##STR398##                      __________________________________________________________________________

                                      TABLE 10                                     __________________________________________________________________________      ##STR399##                                                                                                 m.p.                                                                               yield                                         Ex.                                                                               R.sup.2                                                                          R.sup.5     R.sup.6     (°C.)                                                                       (%)                                                                               Mass NMR                note               __________________________________________________________________________     310                                                                               Cl                                                                                ##STR400##                                                                                 ##STR401## >250                                                                               100                                                                                ##STR402##                                                                          ##STR403##                           311                                                                               Cl                                                                               Cl                                                                                          ##STR404##                                                                                 ##STR405##                                                                        43                                                                                 ##STR406##                                                                          ##STR407##                           __________________________________________________________________________

                                      TABLE 11                                     __________________________________________________________________________      ##STR408##                                                                                                    m.p.                                                                               yield                                      Ex.                                                                               R.sup.2                                                                          R.sup.5        R.sup.6     (°C.)                                                                       (%)                                                                               Mass  NMR           note                __________________________________________________________________________     312                                                                               Cl                                                                                ##STR409##                                                                                    ##STR410##                                                                                 ##STR411##                                                                        91                                                                                 ##STR412##                                                                           ##STR413##                                                                                   ##STR414##         313                                                                               Cl                                                                                ##STR415##                                                                                    ##STR416##                                                                                 ##STR417##                                                                        56                                                                                 ##STR418##                                                                           ##STR419##                       __________________________________________________________________________

                                      TABLE 12                                     __________________________________________________________________________      ##STR420##                                                                                                           m.p.                                                                               yield                               Ex.                                                                               R.sup.2                                                                          R.sup.5        R.sup.6            (°C.)                                                                       (%)                                                                               Mass  NMR     note               __________________________________________________________________________     314                                                                               Cl                                                                                ##STR421##                                                                                    ##STR422##                                                                                        ##STR423##                                                                        68                                                                                 ##STR424##                                                                           ##STR425##                315                                                                               Cl                                                                                ##STR426##                                                                                    ##STR427##                                                                                        ##STR428##                                                                        68                                                                                 ##STR429##                                                                           ##STR430##                __________________________________________________________________________

                                      TABLE 13                                     __________________________________________________________________________      ##STR431##                                                                                                      m.p.                                                                               yield                                    Ex.                                                                               R.sup.2                                                                           R.sup.5     R.sup.6         (°C.)                                                                       (%) Mass                                                                               NMR           note               __________________________________________________________________________     316                                                                               CN                                                                                 ##STR432##                                                                                 ##STR433##                                                                                     ##STR434##                                                                         ##STR435##                                                                         ##STR436##                                                                         ##STR437##                      __________________________________________________________________________

                                      TABLE 14                                     __________________________________________________________________________      ##STR438##                                                                                                    m.p.                                                                               yield                                      Ex.                                                                               R.sup.2                                                                          R.sup.5     R.sup.6        (°C.)                                                                       (%) Mass  NMR           note               __________________________________________________________________________     317                                                                               Cl                                                                                ##STR439##                                                                                 ##STR440##                                                                                    ##STR441##                                                                         ##STR442##                                                                         ##STR443##                                                                           ##STR444##                      318                                                                               Cl                                                                                ##STR445##                                                                                 ##STR446##                                                                                    ##STR447##                                                                        92                                                                                  ##STR448##                                                                           ##STR449##                      __________________________________________________________________________

                                      TABLE 15                                     __________________________________________________________________________      ##STR450##                                                                                          m.p. yield                                               Ex.                                                                               R.sup.2                                                                          R.sup.5                                                                          R.sup.6        (°C.)                                                                        (%)                                                                               Mass    NMR             note                     __________________________________________________________________________     319                                                                               Cl                                                                               Cl                                                                                ##STR451##    193-194                                                                             58 350 (M + 1).sup.+                                                                       ##STR452##                              __________________________________________________________________________

                                      TABLE 16                                     __________________________________________________________________________      ##STR453##                                                                                                    m.p.                                                                               yield                                      Ex.                                                                               R.sup.2                                                                          R.sup.5     R.sup.6        (°C.)                                                                       (%)                                                                               Mass  NMR            note               __________________________________________________________________________     320                                                                               Cl                                                                                ##STR454##                                                                                 ##STR455##                                                                                    ##STR456##                                                                        78                                                                                 ##STR457##                                                                           ##STR458##                       321                                                                               Cl                                                                                ##STR459##                                                                                 ##STR460##                                                                                    ##STR461##                                                                        91                                                                                 ##STR462##                                                                           ##STR463##                       __________________________________________________________________________

                                      TABLE 17                                     __________________________________________________________________________      ##STR464##                                                                                                   m.p.                                                                               yield                                       Ex.                                                                               R.sup.2                                                                          R.sup.5     R.sup.6       (°C.)                                                                       (%)                                                                               Mass  NMR            note                __________________________________________________________________________     322                                                                               Cl                                                                                ##STR465##                                                                                 ##STR466##   >260                                                                               99                                                                                 ##STR467##                                                                           ##STR468##                                                                                    ##STR469##         323                                                                               Cl                                                                                ##STR470##                                                                                 ##STR471##   >260                                                                               65                                                                                 ##STR472##                                                                           ##STR473##                                                                                    ##STR474##         __________________________________________________________________________

                                      TABLE 18                                     __________________________________________________________________________      ##STR475##                                                                                                    m.p.                                                                               yield                                      Ex.                                                                               R.sup.2                                                                          R.sup.5     R.sup.6        (°C.)                                                                       (%)                                                                               Mass  NMR            note               __________________________________________________________________________     324                                                                               Cl                                                                                ##STR476##                                                                                 ##STR477##                                                                                    ##STR478##                                                                        25                                                                                 ##STR479##                                                                           ##STR480##                       325                                                                               Cl                                                                               Cl                                                                                          ##STR481##                                                                                    ##STR482##                                                                        77                                                                                 ##STR483##                                                                           ##STR484##                       __________________________________________________________________________

                                      TABLE 19                                     __________________________________________________________________________      ##STR485##                                                                                                   m.p.                                                                              yield                                        Ex.                                                                               R.sup.2                                                                          R.sup.5     R.sup.6       (°C.)                                                                      (%)                                                                               Mass  NMR             note                __________________________________________________________________________     326                                                                               Cl                                                                                ##STR486##                                                                                 ##STR487##                                                                                   ##STR488##                                                                       76                                                                                 ##STR489##                                                                           ##STR490##                                                                                     ##STR491##         327                                                                               Cl                                                                               Cl                                                                                          ##STR492##                                                                                   ##STR493##                                                                       71                                                                                 ##STR494##                                                                           ##STR495##                         __________________________________________________________________________

                                      TABLE 20                                     __________________________________________________________________________      ##STR496##                                                                                                   m.p.                                                                               yield                                       Ex.                                                                               R.sup.2                                                                          R.sup.5     R.sup.6       (°C.)                                                                       (%)                                                                               Mass  NMR            note                __________________________________________________________________________     328                                                                               Cl                                                                                ##STR497##                                                                                 ##STR498##                                                                                   ##STR499##                                                                        73                                                                                 ##STR500##                                                                           ##STR501##                                                                                    ##STR502##         329                                                                               Cl                                                                                ##STR503##                                                                                 ##STR504##   >260                                                                               65                                                                                 ##STR505##                                                                           ##STR506##                                                                                    ##STR507##         __________________________________________________________________________

                                      TABLE 21                                     __________________________________________________________________________      ##STR508##                                                                                                        m.p.                                                                               yield                                  Ex.                                                                               R.sup.2                                                                           R.sup.5     R.sup.6           (°C.)                                                                       (%)                                                                               Mass  NMR        note               __________________________________________________________________________     330                                                                               OMe                                                                               H                                                                                           ##STR509##                                                                                       ##STR510##                                                                        85                                                                                       ##STR511##                   331                                                                               Cl                                                                                 ##STR512##                                                                                 ##STR513##                                                                                       ##STR514##                                                                        83                                                                                 ##STR515##                                                                           ##STR516##                   __________________________________________________________________________

                                      TABLE 22                                     __________________________________________________________________________      ##STR517##                                                                                                       m.p.                                                                              yield                                    Ex.                                                                               R.sup.2                                                                          R.sup.5     R.sup.6           (°C.)                                                                      (%)                                                                               Mass  NMR         note                __________________________________________________________________________     332                                                                               Cl                                                                                ##STR518##                                                                                 ##STR519##                                                                                       ##STR520##                                                                       97                                                                                 ##STR521##                                                                           ##STR522##                                                                                 ##STR523##         333                                                                               Cl                                                                               Cl                                                                                          ##STR524##       148- 149                                                                          87                                                                                 ##STR525##                                                                           ##STR526##                     __________________________________________________________________________

                                      TABLE 23                                     __________________________________________________________________________      ##STR527##                                                                                                      m.p.                                                                               yield                                    Ex.                                                                               R.sup.2                                                                           R.sup.5     R.sup.6         (°C.)                                                                       (%)                                                                               Mass  NMR          note               __________________________________________________________________________     334                                                                               Cl                                                                                 ##STR528##                                                                                 ##STR529##                                                                                     ##STR530##                                                                        60                                                                                 ##STR531##                                                                           ##STR532##                     335                                                                               CN                                                                                 ##STR533##                                                                                 ##STR534##                                                                                     ##STR535##                                                                        40                                                                                 ##STR536##                                                                           ##STR537##                     __________________________________________________________________________

                                      TABLE 24                                     __________________________________________________________________________      ##STR538##                                                                                            m.p. yield                                             Ex.                                                                               R.sup.2                                                                           R.sup.5                                                                          R.sup.6         (°C.)                                                                        (%)                                                                               Mass  NMR              note                    __________________________________________________________________________     336                                                                               CN Cl                                                                                ##STR539##     156-158                                                                             89 353 (MH.sup.+)                                                                        ##STR540##                              337                                                                               CN Cl                                                                                ##STR541##     173-175                                                                             86 373 (MH.sup.+)                                                                        ##STR542##                              __________________________________________________________________________

                                      TABLE 25                                     __________________________________________________________________________      ##STR543##                                                                                                     m.p.                                                                              yield                                      Ex.                                                                               R.sup.2                                                                          R.sup.5      R.sup.6        (°C.)                                                                      (%)                                                                               Mass  NMR            note               __________________________________________________________________________     338                                                                               Cl                                                                               COOH                                                                                         ##STR544##                                                                                    ##STR545##                                                                       93                                                                                 ##STR546##                                                                           ##STR547##                       339                                                                               Cl                                                                                ##STR548##                                                                                  ##STR549##                                                                                    ##STR550##                                                                       99                                                                                 ##STR551##                                                                           ##STR552##                       __________________________________________________________________________

                                      TABLE 26                                     __________________________________________________________________________      ##STR553##                                                                                                      m.p.                                                                               yield                                    Ex.                                                                               R.sup.2                                                                          R.sup.5     R.sup.6          (°C.)                                                                       (%)                                                                               Mass  NMR         note                __________________________________________________________________________     340                                                                               Cl                                                                                ##STR554##                                                                                 ##STR555##                                                                                      ##STR556##                                                                        88                                                                                 ##STR557##                                                                           ##STR558##                                                                                 ##STR559##         341                                                                               Cl                                                                                ##STR560##                                                                                 ##STR561##                                                                                      ##STR562##                                                                        75                                                                                 ##STR563##                                                                           ##STR564##                     __________________________________________________________________________

                                      TABLE 27                                     __________________________________________________________________________      ##STR565##                                                                                                     m.p.                                                                               yield                                     Ex.                                                                               R.sup.2                                                                          R.sup.5       R.sup.6       (°C.)                                                                       (%)                                                                               Mass  NMR          note                __________________________________________________________________________     342                                                                               Cl                                                                                ##STR566##                                                                                   ##STR567##                                                                                   ##STR568##                                                                        95                                                                                 ##STR569##                                                                           ##STR570##                                                                                  ##STR571##         343                                                                               Cl                                                                                ##STR572##                                                                                   ##STR573##                                                                                   ##STR574##                                                                        41                                                                                 ##STR575##                                                                           ##STR576##                                                                                  ##STR577##         __________________________________________________________________________

                                      TABLE 28                                     __________________________________________________________________________      ##STR578##                                                                                                      m.p.                                                                               yield                                    Ex.                                                                               R.sup.2                                                                           R.sup.5       R.sup.6       (°C.)                                                                       (%)                                                                               Mass  NMR          note               __________________________________________________________________________     344                                                                               Cl                                                                                 ##STR579##                                                                                   ##STR580##                                                                                   ##STR581##                                                                        81                                                                                 ##STR582##                                                                           ##STR583##                     345                                                                               CN Cl                                                                                            ##STR584##                                                                                   ##STR585##                                                                        78                                                                                 ##STR586##                                                                           ##STR587##                     __________________________________________________________________________

                                      TABLE 29                                     __________________________________________________________________________      ##STR588##                                                                                                           m.p.                                                                               yield                               Ex.                                                                               R.sup.2                                                                           R.sup.5     R.sup.6              (°C.)                                                                       (%)                                                                               Mass  NMR     note               __________________________________________________________________________     346                                                                               CN                                                                                 ##STR589##                                                                                 ##STR590##                                                                                          ##STR591##                                                                        82                                                                                 ##STR592##                                                                           ##STR593##                347                                                                               Cl                                                                                 ##STR594##                                                                                 ##STR595##                                                                                          ##STR596##                                                                        19                                                                                 ##STR597##                                                                           ##STR598##                __________________________________________________________________________

                                      TABLE 30                                     __________________________________________________________________________      ##STR599##                                                                                                        m.p.                                                                               yield                                  Ex.                                                                               R.sup.2                                                                           R.sup.5          R.sup.6      (°C.)                                                                       (%)                                                                               Mass NMR         note               __________________________________________________________________________     348                                                                               NC                                                                                 ##STR600##                                                                                      ##STR601##  >250                                                                               62                                                                                      ##STR602##                    349                                                                               Cl                                                                                 ##STR603##                                                                                      ##STR604##                                                                                  ##STR605##                                                                        95                                                                                 ##STR606##                                                                          ##STR607##                    __________________________________________________________________________

                                      TABLE 31                                     __________________________________________________________________________      ##STR608##                                                                                              m.p. yield                                           Ex.                                                                               R.sup.2                                                                           R.sup.3                                                                           R.sup.4                                                                           R.sup.6       (°C.)                                                                        (%)                                                                               Mass    NMR               note               __________________________________________________________________________     350                                                                               MeO                                                                               MeO                                                                               MeO                                                                                ##STR609##   163-164                                                                             70 362 (M + 1).sup.+                                                                       ##STR610##                          351                                                                               MeO                                                                               MeO                                                                               MeO                                                                                ##STR611##   173-174                                                                             37 376 (M + 1).sup.+                                                                       ##STR612##                          352                                                                               MeO                                                                               MeO                                                                               MeO                                                                                ##STR613##   170-171                                                                             70 362 (M + 1).sup.+                                                                       ##STR614##                          __________________________________________________________________________

                                      TABLE 32                                     __________________________________________________________________________      ##STR615##                                                                                              m.p. yield                                           Ex.                                                                               R.sup.2                                                                           R.sup.3                                                                           R.sup.4                                                                           R.sup.6       (°C.)                                                                        (%)                                                                               Mass    NMR               note               __________________________________________________________________________     353                                                                               MeO                                                                               MeO                                                                               MeO                                                                                ##STR616##   143-144                                                                             24 376 (M + 1).sup.+                                                                       ##STR617##                          354                                                                               MeO                                                                               MeO                                                                               MeO                                                                                ##STR618##   139-140                                                                             88 303 (M + 1).sup.+                                                                       ##STR619##                          355                                                                               MeO                                                                               MeO                                                                               MeO                                                                                ##STR620##   160-161                                                                             94 317 (M + 1).sup.+                                                                       ##STR621##                          __________________________________________________________________________

                                      TABLE 33                                     __________________________________________________________________________      ##STR622##                                                                                              m.p. yield                                           Ex.                                                                               R.sup.2                                                                           R.sup.3                                                                           R.sup.4                                                                           R.sup.6       (°C.)                                                                        (%)                                                                               Mass    NMR               note               __________________________________________________________________________     356                                                                               MeO                                                                               MeO                                                                               MeO                                                                                ##STR623##   155-156                                                                             75 331 (M + 1).sup.+                                                                       ##STR624##                          __________________________________________________________________________

                                      TABLE 34                                     __________________________________________________________________________      ##STR625##                                                                                                m.p. yield                                         Ex.                                                                               R.sup.2                                                                          R.sup.5                (°C.)                                                                        (%)                                                                               Mass NMR                note               __________________________________________________________________________     357                                                                               Cl                                                                                ##STR626##            225-227                                                                             85                                                                                 ##STR627##                                                                          ##STR628##                           358                                                                               Cl                                                                                ##STR629##                                                                                            ##STR630##                                                                         32                                                                                 ##STR631##                                                                          ##STR632##                           __________________________________________________________________________

                                      TABLE 35                                     __________________________________________________________________________      ##STR633##                                                                                             m.p.                                                                              yield                                              Ex.                                                                               R.sup.2                                                                          R.sup.5             (°C.)                                                                      (%)                                                                               Mass  NMR                   note                __________________________________________________________________________     359                                                                               Cl                                                                                ##STR634##                                                                                         ##STR635##                                                                       95                                                                                 ##STR636##                                                                           ##STR637##                               360                                                                               Cl                                                                                ##STR638##                                                                                         ##STR639##                                                                       98                                                                                 ##STR640##                                                                           ##STR641##                               361                                                                               Cl                                                                                ##STR642##                                                                                         ##STR643##                                                                       93                                                                                 ##STR644##                                                                           ##STR645##                                                                                           ##STR646##         __________________________________________________________________________

                                      TABLE 36                                     __________________________________________________________________________      ##STR647##                                                                                       m.p. yield                                                  Ex.                                                                               R.sup.2                                                                          R.sup.5       (°C.)                                                                        (%)                                                                               Mass   NMR                  note                    __________________________________________________________________________     362                                                                               Cl                                                                                ##STR648##        12                                                                                        ##STR649##                                  363                                                                               H Cl            191-192                                                                             94 314 (M + 1)                                                                            ##STR650##                                  __________________________________________________________________________

                                      TABLE 37                                     __________________________________________________________________________      ##STR651##                                                                                     m.p. yield                                                    Ex.                                                                               R.sup.2                                                                          R.sup.5     (°C.)                                                                        (%)                                                                               Mass   NMR                    note                    __________________________________________________________________________     364                                                                               H                                                                                 ##STR652## 159-161                                                                             97 407 (M + 1)                                                                            ##STR653##                                    365                                                                               Cl                                                                                ##STR654## 243-245                                                                             81 455 (M + 1)                                                                            ##STR655##                                    __________________________________________________________________________

                                      TABLE 38                                     __________________________________________________________________________      ##STR656##                                                                                           m.p.                                                                               yield                                               Ex.                                                                               R.sup.2                                                                          R.sup.5           (°C.)                                                                       (%) Mass  NMR                   note                __________________________________________________________________________     366                                                                               Cl                                                                                ##STR657##                                                                                       ##STR658##                                                                        99                                                                                  ##STR659##                                                                           ##STR660##                               367                                                                               Cl                                                                                ##STR661##                                                                                       ##STR662##                                                                         ##STR663##                                                                         ##STR664##                                                                           ##STR665##                                                                                           ##STR666##         __________________________________________________________________________

                                      TABLE 39                                     __________________________________________________________________________      ##STR667##                                                                                         m.p.  yield                                               Ex.                                                                               R.sup.2                                                                          R.sup.5         (°C.)                                                                         (%)                                                                               Mass   NMR                    note               __________________________________________________________________________     368                                                                               Cl                                                                                ##STR668##     193-195                                                                              86 456 (M + 1)                                                                            ##STR669##                               369                                                                               Cl                                                                                ##STR670##     174-176                                                                              90 470 (M + 1)                                                                            ##STR671##                               370                                                                               Cl                                                                                ##STR672##                                                                                     ##STR673##                                                                          80 461 (MH.sup.+)                                                                         ##STR674##                               __________________________________________________________________________

                                      TABLE 40                                     __________________________________________________________________________      ##STR675##                                                                                     m.p.  yield                                                   Ex.                                                                               R.sup.2                                                                          R.sup.5     (°C.)                                                                         (%)                                                                               Mass  NMR                    note                    __________________________________________________________________________     371                                                                               Cl                                                                                ##STR676##                                                                                 ##STR677##                                                                          42 401 (MH.sup.+)                                                                        ##STR678##                                    372                                                                               Cl                                                                                ##STR679##                                                                                 ##STR680##                                                                             424 (MH.sup.+)                                                                        ##STR681##                                    __________________________________________________________________________

                                      TABLE 41                                     __________________________________________________________________________      ##STR682##                                                                                     m.p. yield                                                    Ex.                                                                               R.sup.2                                                                          R.sup.5     (°C.)                                                                        (%)                                                                               Mass    NMR                    note                   __________________________________________________________________________     373                                                                               Br                                                                               Cl          213-214                                                                             80 392 (M + 1).sup.+                                                                       ##STR683##                                   374                                                                               F Cl          192-193                                                                             80 332 (M + 1).sup.+                                                                       ##STR684##                                   375                                                                               Br                                                                                ##STR685## 239-240                                                                             80 513 (M + 1).sup.+                                                                       ##STR686##            hydrochloride          __________________________________________________________________________

                                      TABLE 42                                     __________________________________________________________________________      ##STR687##                                                                                          m.p. yield                                               Ex.                                                                               R.sup.2                                                                               R.sup.5     (°C.)                                                                        (%)                                                                               Mass  NMR                     note               __________________________________________________________________________     376                                                                               Br                                                                                     ##STR688## 209-210                                                                             96                                                                                 ##STR689##                                                                           ##STR690##                                377                                                                                ##STR691##                                                                           Cl          200-201                                                                             36                                                                                 ##STR692##                                                                           ##STR693##                                __________________________________________________________________________

                                      TABLE 43                                     __________________________________________________________________________      ##STR694##                                                                                               m.p.                                                                               yield                                           Ex.                                                                               R.sup.2                                                                              R.sup.5           (°C.)                                                                       (%)                                                                               Mass  NMR                 note               __________________________________________________________________________     378                                                                                ##STR695##                                                                          Cl                                                                                                ##STR696##                                                                        94                                                                                 ##STR697##                                                                           ##STR698##                            379                                                                               Cl                                                                                    ##STR699##                                                                                       ##STR700##                                                                        86                                                                                 ##STR701##                                                                           ##STR702##                            __________________________________________________________________________

                                      TABLE 44                                     __________________________________________________________________________      ##STR703##                                                                                         m.p. yield                                                Ex.                                                                               R.sup.2                                                                          R.sup.5         (°C.)                                                                        (%)                                                                               Mass   NMR                     note               __________________________________________________________________________     380                                                                               Cl                                                                                ##STR704##     193-195                                                                             85 484 (M + 1)                                                                            ##STR705##                                381                                                                               Cl                                                                                ##STR706##     204-205                                                                             62 468 (M + 1)                                                                            ##STR707##                                __________________________________________________________________________

                                      TABLE 45                                     __________________________________________________________________________      ##STR708##                                                                                     m.p. yield                                                    Ex.                                                                               R.sup.2                                                                          R.sup.5     (°C.)                                                                        (%)                                                                               Mass    NMR                    note                   __________________________________________________________________________     382                                                                               Cl                                                                                ##STR709## 233-234                                                                             93 455 (M + 1).sup.+                                                                       ##STR710##            hydrochloride          383                                                                               Cl                                                                                ##STR711##                                                                                 ##STR712##                                                                         99 469 (M + 1).sup.+                                                                       ##STR713##                                   __________________________________________________________________________

                                      TABLE 46                                     __________________________________________________________________________      ##STR714##                                                                                   m.p.  yield                                                     Ex.                                                                               R.sup.2                                                                          R.sup.5   (°C.)                                                                         (%)                                                                               Mass    NMR                   note                     __________________________________________________________________________     384                                                                               Cl                                                                                ##STR715##                                                                               ##STR716##                                                                          98 441 (M + 1).sup.+                                                                       ##STR717##                                    385                                                                               Cl                                                                               CN        198-199                                                                              35 339 (M + 1).sup.+                                                                       ##STR718##                                    __________________________________________________________________________

                                      TABLE 47                                     __________________________________________________________________________      ##STR719##                                                                                         m.p. yield                                                Ex.                                                                               R.sup.2                                                                              R.sup.5     (°C.)                                                                        (%)                                                                               Mass    NMR                    note               __________________________________________________________________________     386                                                                               MeS   H           174-175                                                                             83 326 (M + H).sup.+                                                                       ##STR720##                               387                                                                                ##STR721##                                                                          H           154-155                                                                             80 342 (M + H).sup.+                                                                       ##STR722##                               388                                                                               Cl                                                                                    ##STR723## 154-155                                                                             71 401 (M + 1).sup.+                                                                       ##STR724##                               __________________________________________________________________________

                                      TABLE 48                                     __________________________________________________________________________      ##STR725##                                                                                          m.p.  yield                                              Ex.                                                                               R.sup.2                                                                           R.sup.5         (°C.)                                                                         (%)                                                                               Mass  NMR                    note               __________________________________________________________________________     389                                                                               Cl Cl                                                                                              ##STR726##                                                                          48                                                                                 ##STR727##                                                                           ##STR728##                               390                                                                               CN                                                                                 ##STR729##                                                                                     ##STR730##                                                                          29 455 (MH.sup.+)                                                                        ##STR731##                               391                                                                               CN                                                                                 ##STR732##     176-179                                                                              35 469 (MH.sup.+)                                                                        ##STR733##                               __________________________________________________________________________

                                      TABLE 49                                     __________________________________________________________________________      ##STR734##                                                                                             m.p.  yield                                           Ex.                                                                               R.sup.2                                                                          R.sup.5             (°C.)                                                                         (%)                                                                               Mass NMR                  note               __________________________________________________________________________     392                                                                               Cl                                                                                ##STR735##                                                                                         ##STR736##                                                                          51                                                                                      ##STR737##                             393                                                                               Cl                                                                                ##STR738##         255-256                                                                              96                                                                                 ##STR739##                                                                          ##STR740##                             __________________________________________________________________________

                                      TABLE 50                                     __________________________________________________________________________      ##STR741##                                                                                        m.p.  yield                                                Ex.                                                                               R.sup.2                                                                          R.sup.5        (°C.)                                                                         (%) Mass    NMR                   note               __________________________________________________________________________     394                                                                               Cl                                                                                ##STR742##    222-223                                                                              13  317 (M + 1)                                                                             ##STR743##                              395                                                                               Cl                                                                                ##STR744##    176-177                                                                              54  463 (M + 1)                                                                             ##STR745##                              __________________________________________________________________________

                                      TABLE 51                                     __________________________________________________________________________      ##STR746##                                                                                          m.p.  yield                                              Ex.                                                                               R.sup.2                                                                           R.sup.5         (°C.)                                                                         (%)                                                                               Mass  NMR                    note               __________________________________________________________________________     396                                                                               CN                                                                                 ##STR747##     176-179                                                                              35 469 (MH.sup.+)                                                                        ##STR748##                               397                                                                               CN                                                                                 ##STR749##                                                                                     ##STR750##                                                                          29 455 (MH.sup.+)                                                                        ##STR751##                               __________________________________________________________________________

                                      TABLE 52                                     __________________________________________________________________________      ##STR752##                                                                                       m.p.  yield                                                 Ex.                                                                               R.sup.2                                                                          R.sup.5       (°C.)                                                                         (%)                                                                               Mass   NMR                    note                 __________________________________________________________________________     398                                                                               Cl                                                                                ##STR753##   236-237                                                                              27 485 (M + 1)                                                                            ##STR754##                                                                                            ##STR755##          399                                                                               Cl                                                                                ##STR756##                                                                                   ##STR757##                                                                          78 457 (M + 1)                                                                            ##STR758##                                 __________________________________________________________________________

                                      TABLE 53                                     __________________________________________________________________________      ##STR759##                                                                                         m.p.  yield                                               Ex.                                                                               R.sup.2                                                                           R.sup.5        (°C.)                                                                         (%)                                                                               Mass   NMR                    note               __________________________________________________________________________     400                                                                               Cl                                                                                 ##STR760##    148-150                                                                              21 443 (M + 1)                                                                            ##STR761##                               401                                                                               Cl                                                                                 ##STR762##                                                                                    ##STR763##                                                                          80 485 (MH.sup.+)                                                                         ##STR764##                               __________________________________________________________________________

                                      TABLE 54                                     __________________________________________________________________________      ##STR765##                                                                                     m.p.  yield                                                   Ex.                                                                               R.sup.2                                                                          R.sup.5     (°C.)                                                                         (%)                                                                               Mass  NMR                  note                      __________________________________________________________________________     402                                                                               Cl                                                                                ##STR766##                                                                                 ##STR767##                                                                          62 470 (MH.sup.+)                                                                        ##STR768##                                    403                                                                               Cl                                                                                ##STR769##                                                                                 ##STR770##                                                                          58 425 (MH.sup.+)                                                                        ##STR771##                                    __________________________________________________________________________

                                      TABLE 55                                     __________________________________________________________________________      ##STR772##                                                                                      m.p.  yield                                                  Ex.                                                                               R.sup.2                                                                          R.sup.5      (°C.)                                                                         (%)                                                                               Mass   NMR                  note                    __________________________________________________________________________     404                                                                               Cl                                                                                ##STR773##                                                                                  ##STR774##                                                                             344 (MH.sup.+)                                                                         ##STR775##                                  405                                                                               Cl                                                                                ##STR776##  191-192                                                                              97 400 (M + 1)                                                                            ##STR777##                                  __________________________________________________________________________

                                      TABLE 56                                     __________________________________________________________________________      ##STR778##                                                                                       m.p. yield                                                  Ex.                                                                               R.sup.2                                                                           R.sup.5      (°C.)                                                                        (%)                                                                               Mass   NMR                  note                    __________________________________________________________________________     406                                                                               CN                                                                                 ##STR779##  245-246                                                                             55 391 (M + 1)                                                                            ##STR780##                                  407                                                                               Cl                                                                                 ##STR781##  201-202                                                                             99 386 (M + 1)                                                                            ##STR782##                                  __________________________________________________________________________

                                      TABLE 57                                     __________________________________________________________________________      ##STR783##                                                                                         m.p.  yield                                               Ex.                                                                               R.sup.2                                                                          R.sup.5         (°C.)                                                                         (%)                                                                               Mass  NMR                    note                __________________________________________________________________________     408                                                                               Cl                                                                                ##STR784##                                                                                     ##STR785##                                                                          79                                                                                 ##STR786##                                                                           ##STR787##                                                                                            ##STR788##         409                                                                               Cl                                                                                ##STR789##                                                                                     ##STR790##                                                                          81 505 (MH.sup.+)                                                                        ##STR791##                                __________________________________________________________________________

                                      TABLE 58                                     __________________________________________________________________________      ##STR792##                                                                                         m.p.   yield                                              Ex.                                                                               R.sup.2                                                                          R.sup.5         (°C.)                                                                          (%) Mass  NMR                   note               __________________________________________________________________________     410                                                                               Cl                                                                                ##STR793##                                                                                     ##STR794##                                                                           91  477 (MH.sup.+)                                                                        ##STR795##                              __________________________________________________________________________ 

We claim:
 1. A compound, or the pharmacologically acceptable salt thereof, represented by the formula (I): ##STR796## wherein R1, R3, and R4, each of which may be the same or different from each other, may each represent a hydrogen atom, a halogen atom or a lower alkyl group or a lower alkoxy hydrogen atom, R2 is a halogen or cyan group R5 is a group represented by the formula: ##STR797## wherein u is 3 or 4 and R61 represents a carboxyl group which may be protected or a heteroaryl group; or R5 is a group represented by the formula: ##STR798## and R6 is a group represented by the formula ##STR799## wherein X is hydrogen atom or a halogen atom or ##STR800##
 2. The compound or the pharmacologically acceptable salt thereof as set forth in claim 1, wherein R⁵ is a group represented by the formula ##STR801## wherein R⁶¹ represents a carboxyl group which may be protected or a heteroaryl group.
 3. The compound or the pharmacologically acceptable salt thereof as set forth in claim 1, wherein R⁵ is a group represented by the formula ##STR802## wherein R⁶¹ represents a carboxyl group which may be protected; and u represents 3 or
 4. 4. The compound or the pharmacologically acceptable salt thereof as set forth in claim 1, wherein R² is a cyano group.
 5. The compound or the pharmacologically acceptable salt thereof as set forth in claim 1, wherein R¹, R³ and R⁴ are hydrogen atoms; R² is a chlorine atom; R⁵ is a group represented by the formula ##STR803## and R⁶ is a group represented by the formula ##STR804##
 6. The compound or the pharmacologically acceptable salt thereof as set forth in claim 1, wherein R¹, R³ and R⁴ are hydrogen atoms; R² is a cyano group; R⁵ is a group represented by the formula ##STR805## and R⁶ is a group represented by the formula ##STR806##
 7. The compound of the pharmacologically acceptable salt thereof as set forth in claim 1, wherein R¹, R³ and R⁴ are hydrogen atoms; R² is a cyano group; R⁵ is a group represented by the formula ##STR807## wherein R⁶¹ represents a carboxyl group which may be protected; and R⁶ is a group represented by the formula ##STR808##
 8. A pharmaceutical composition comprising a compound or the pharmaceutically acceptable salt thereof as set forth in claim 1 together with a pharmaceutically acceptable carrier or diluent.
 9. A method of treating a condition selected from the group consisting of ischemic heart disease, angina pectoris, hypertension, heart failure and asthma comprising administering to a person in need of same an effective amount of the compound of claim
 1. 10. 2-(4-carboxypiperidino)-4-(3,4-methylene-dioxybenzyl) amino-6-chloroquinazoline- or a pharmaceutically acceptable salt thereof.
 11. Sodium 2-( 4-carboxypiperidino)-4-(3,4-methylene-dioxybenzyl) amino-6-chloroquinazoline. 